{"gene":"ABCC10","run_date":"2026-06-09T22:02:36","timeline":{"discoveries":[{"year":2001,"finding":"MRP7/ABCC10 is a 1492 amino acid ABC transporter with three membrane-spanning domains (structural architecture resembling MRP1/2/3/6), confirmed by synthesis of an ~158 kDa protein in reticulocyte lysates programmed with the MRP7 cDNA, and maps to chromosome 6p12-21.","method":"cDNA sequence analysis, reticulocyte lysate in vitro translation, fluorescence in situ hybridization","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 1 (in vitro translation confirming protein product) / Weak — single lab, foundational structural characterization","pmids":["11146224"],"is_preprint":false},{"year":2003,"finding":"ABCC10/MRP7 mediates MgATP-dependent transport of the amphipathic anion 17β-estradiol-17β-D-glucuronide (E2 17βG) with Km ~57.8 µM and Vmax ~53.1 pmol/mg/min in membrane vesicles; LTC4 is a potent competitive inhibitor (Ki ~1.5 µM), and the pump shows modest LTC4 transport but not other canonical MRP substrates tested.","method":"Membrane vesicle transport assay using HEK293 cells transfected with MRP7 expression vector; competitive inhibition kinetics","journal":"Molecular pharmacology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstituted vesicle transport with kinetic parameters, single lab but multiple substrates and inhibitors tested rigorously","pmids":["12527806"],"is_preprint":false},{"year":2004,"finding":"ABCC10/MRP7 overexpression in HEK293 cells confers resistance to docetaxel (9–13-fold), paclitaxel (3-fold), vincristine (3-fold), and vinblastine (3–4-fold); MRP7-transfected cells show reduced accumulation of radiolabeled paclitaxel, consistent with ATP-dependent efflux pump activity.","method":"Ectopic expression in HEK293 cells, cytotoxicity assays, radiolabeled drug accumulation assay","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean overexpression with defined phenotypic readout and accumulation assay; independently replicated across multiple subsequent studies","pmids":["15256465"],"is_preprint":false},{"year":2009,"finding":"ABCC10/MRP7 confers resistance to nucleoside analogues (cytarabine/Ara-C, gemcitabine, 2',3'-dideoxycytidine, PMEA) and epothilone B in addition to taxanes and vinca alkaloids; buthionine sulfoximine did not attenuate MRP7-conferred resistance, indicating MRP7-mediated transport does not involve glutathione (unlike MRP1/2).","method":"MRP7-transfected HEK293 cells and mouse embryo fibroblasts deficient in P-gp and Mrp1; cytotoxicity and radiolabeled drug accumulation assays","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple drug classes tested in two independent cellular backgrounds with accumulation assays; glutathione-independence confirmed by BSO experiment","pmids":["19118001"],"is_preprint":false},{"year":2011,"finding":"Abcc10 knockout mice show that Abcc10 is an endogenous resistance factor in vivo: Abcc10−/− mouse embryo fibroblasts are hypersensitive to docetaxel, paclitaxel, vincristine, and Ara-C with increased drug accumulation; Abcc10−/− mice treated with paclitaxel exhibit increased lethality with neutropenia and bone marrow/spleen/thymus toxicity.","method":"Abcc10−/− mouse generation, MEF cytotoxicity/accumulation assays, in vivo paclitaxel treatment with pathological assessment","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout mouse model with in vivo and in vitro phenotypic readouts, first demonstration of in vivo relevance","pmids":["21576088"],"is_preprint":false},{"year":2012,"finding":"ABCC10 substrates E2 17βG and LTC4 stimulate ABCC10 BeFx-sensitive ATPase activity; tamoxifen is identified as a novel substrate and ATPase stimulator; docetaxel, paclitaxel, and Ara-C also increase basal ATPase activity. ABCC10 localizes to the basolateral cell surface and exports docetaxel from apical to basolateral side in transepithelial LLC-PK1 assays. Sorafenib and cepharanthine inhibit ABCC10 docetaxel transport activity.","method":"Crude membrane ATPase assays with BeFx (vanadate-sensitive controls), transepithelial well assay in ABCC10-overexpressing LLC-PK1 cells, radiolabeled docetaxel transport","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — biochemical ATPase reconstitution, vectorial transport in polarized cells, and subcellular localization all in one study with functional consequence","pmids":["23087055"],"is_preprint":false},{"year":2008,"finding":"Sulfinpyrazone (an ABCC10 inhibitor) alters sensitivity to paclitaxel in ABCC10-expressing NSCLC cells concomitant with increased intracellular paclitaxel accumulation; siRNA knockdown of ABCC10 enhances paclitaxel cytotoxicity in NCI-H23 cells with increased intracellular paclitaxel, confirming ABCC10 effluxes paclitaxel endogenously in lung cancer cells.","method":"siRNA knockdown in NSCLC cells, pharmacological inhibition with sulfinpyrazone, intracellular paclitaxel accumulation assay","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function (siRNA) and pharmacological inhibition with accumulation readout in endogenous cancer cell context","pmids":["18445659"],"is_preprint":false},{"year":2009,"finding":"Lapatinib and erlotinib (EGFR TKIs) reverse MRP7/ABCC10-mediated multidrug resistance by inhibiting drug efflux function (increased intracellular [3H]-paclitaxel accumulation and decreased efflux in MRP7-transfected cells) without altering MRP7 protein expression levels.","method":"MRP7-transfected HEK293 cells, cytotoxicity assay, [3H]-paclitaxel accumulation and efflux assays, Western blot","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, accumulation/efflux assays demonstrate functional inhibition mechanism","pmids":["19720054"],"is_preprint":false},{"year":2009,"finding":"Imatinib and nilotinib (BCR-Abl TKIs) reverse MRP7/ABCC10-mediated multidrug resistance by inhibiting paclitaxel efflux and increasing intracellular [3H]-paclitaxel accumulation in MRP7-transfected HEK293 cells, without altering MRP7 expression.","method":"MRP7-transfected HEK293 cells, MTT assay, [3H]-paclitaxel accumulation and efflux assays, Western blot","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, accumulation/efflux assays demonstrate functional inhibition of MRP7 transport activity","pmids":["19841739"],"is_preprint":false},{"year":2008,"finding":"Cepharanthine reverses MRP7/ABCC10-mediated paclitaxel resistance and competitively inhibits E2 17βG transport by MRP7 in membrane vesicle assays with a Ki of 4.86 µM, identifying it as a competitive inhibitor of ABCC10.","method":"MRP7-transfected HEK293 cells, paclitaxel accumulation/efflux assays, membrane vesicle E2 17βG transport competitive inhibition assay","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro vesicle transport with kinetic inhibition constants, single lab","pmids":["19150344"],"is_preprint":false},{"year":2011,"finding":"Tenofovir (TFV) is a substrate for ABCC10: TFV accumulation is 35% lower in HEK293-ABCC10 cells than parental HEK293 cells, reversed by cepharanthine; siRNA knockdown of ABCC10 increases TFV accumulation in CD4+ cells (18%) and monocyte-derived macrophages (25%).","method":"ABCC10-transfected HEK293 cells, pharmacological inhibition with cepharanthine, siRNA knockdown in primary CD4+ cells and macrophages, drug accumulation assay","journal":"The Journal of infectious diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression and loss-of-function (siRNA) in two cell types with accumulation readout, pharmacological confirmation","pmids":["21628669"],"is_preprint":false},{"year":2012,"finding":"Nevirapine is a substrate for ABCC10: accumulation is 37% lower in HEK293-ABCC10 cells vs. parental, reversed by cepharanthine; siRNA knockdown increases nevirapine accumulation in CD4+ cells (32%) and monocyte-derived macrophages (38%).","method":"ABCC10-transfected HEK293 cells, siRNA knockdown in CD4+ cells and macrophages, drug accumulation assays, pharmacological inhibition","journal":"Pharmacogenetics and genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression and loss-of-function in primary cells with accumulation readout and pharmacological confirmation","pmids":["22082652"],"is_preprint":false},{"year":2017,"finding":"FOXM1 promotes 5-FU resistance in colorectal cancer by directly binding to the ABCC10 promoter and driving its transcription; ABCC10 inhibition reverses FOXM1-induced 5-FU resistance in vivo.","method":"Chromatin immunoprecipitation (promoter binding), FOXM1 overexpression and silencing in CRC cells, in vivo xenograft with ABCC10 inhibitor","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding demonstrated, functional rescue in vivo, single lab","pmids":["28051999"],"is_preprint":false},{"year":2018,"finding":"ABCC10 actively effluxes gefitinib with an efflux ratio of 7.8 in an in vitro transport assay; overexpression of ABCC10 reduces intracellular gefitinib accumulation and decreases gefitinib sensitivity in NSCLC cells and xenograft models.","method":"In vitro transport assay, ABCC10-overexpressing cell lines, intracellular gefitinib accumulation measurement, in vivo xenograft","journal":"Frontiers in pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transport assay with defined efflux ratio, overexpression in vitro and in vivo, single lab","pmids":["30515095"],"is_preprint":false},{"year":2021,"finding":"Exosomal delivery of the m6A demethylase FTO from gefitinib-resistant cells to recipient cells decreases m6A modification on ABCC10 mRNA, reducing YTHDF2-mediated decay and thereby increasing ABCC10 expression, which mediates gefitinib resistance transfer.","method":"Exosome internalization assays, m6A quantification, FTO knockdown/overexpression, YTHDF2 functional studies, in vitro and in vivo resistance models","journal":"Molecular cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (m6A sequencing, FTO KD, YTHDF2 pathway), single lab, functional in vivo validation","pmids":["33563765"],"is_preprint":false},{"year":2014,"finding":"Abcc10 loss in MMTV-PyVmT mammary tumor mice results in faster tumor growth with reduced apoptosis and reduced metastasis; Abcc10-null tumor-derived cell lines are less migratory; Abcc10−/− mice show increased survival upon docetaxel treatment, confirming in vivo role as docetaxel resistance factor in mammary tumors.","method":"Abcc10−/− x MMTV-PyVmT mouse cross, allograft and cellular assays, migration assays, in vivo docetaxel treatment survival analysis","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO in relevant tumor model with multiple cellular and in vivo readouts, single lab","pmids":["24937672"],"is_preprint":false},{"year":2021,"finding":"ABCC10 homology model (based on cryo-EM structure of MRP1) combined with molecular dynamics simulations and docking identifies predicted substrate- and modulator-binding sites within the transmembrane region of MRP7/ABCC10, with motion patterns consistent with the ABC efflux mechanism.","method":"Homology modeling based on MRP1 cryo-EM structure, molecular dynamics simulation, in silico docking","journal":"MedComm","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational modeling only, no experimental structural validation of binding sites","pmids":["34766143"],"is_preprint":false},{"year":2022,"finding":"LXRα activation by its agonist TO901317 alters ABCC10 gene expression in rat hepatic and cardiac tissues, identifying ABCC10 as a specific LXRα target gene.","method":"In vivo rat hypercholesterolemia model, LXRα agonist treatment, hepatic/cardiac gene expression analysis","journal":"Biochemical and biophysical research communications","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, gene expression readout without direct promoter binding or mechanistic follow-up","pmids":["35462094"],"is_preprint":false},{"year":2023,"finding":"ABCC10 redistributes from plasma membrane to lysosomes in paclitaxel-resistant cancer cells; lysosome-localized ABCC10 (along with ABCC3 and ABCC5) contributes to sequestration of doxorubicin and paclitaxel-OregonGreen488 in lysosomes; siRNA silencing of ABCC10 limits lysosomal drug accumulation.","method":"Western blot and confocal microscopy for localization, siRNA knockdown, ABCC inhibitors, flow cytometry for drug accumulation in lysosomes in paclitaxel-resistant TNBC and NSCLC cells","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — localization tied to functional drug sequestration outcome, loss-of-function confirmation, single lab","pmids":["37767694"],"is_preprint":false},{"year":2023,"finding":"ABCC10 regulates glucosylceramide (GlcCer) synthesis and efflux differentially: sorafenib (ABCC10 inhibitor) decreases both GlcCer synthesis and efflux, while cepharanthine reduces only GlcCer efflux but not synthesis, in Huh-7 liver cells.","method":"Pharmacological inhibition with sorafenib and cepharanthine, GlcCer synthesis and efflux measurement in Huh-7 cells","journal":"Nutrients","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pharmacological inhibition only (no genetic KO/KD confirmation), single lab, mechanistic interpretation indirect","pmids":["36678216"],"is_preprint":false},{"year":2022,"finding":"ABCC10 deletion in mice results in lower plasma and intestinal triglycerides (~38% and 36% reduction), ameliorates diet-induced obesity, reduces oleate uptake by enterocytes (~25–30%), and reduces intestinal triglyceride absorption (~37%), indicating ABCC10 regulates dietary fat absorption.","method":"Abcc10 knockout mice, plasma/intestinal lipid measurements, insulin/glucose tolerance tests, intestinal fat absorption assays","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO mouse model with multiple metabolic readouts, single lab","pmids":["36430292"],"is_preprint":false},{"year":2025,"finding":"ABCC10 binds and effluxes 2'3'-cyclic GMP-AMP (cGAMP) in an ATP-dependent manner at the R545 site; ABCC10-mediated cGAMP export suppresses the STING-TBK1-IRF3 signaling pathway, reducing RT-induced ROS and DNA damage, thereby conferring radiotherapy resistance. Nilotinib (ABCC10 inhibitor) combined with radiotherapy synergistically inhibits tumor growth in vivo.","method":"CRISPR metabolic library screen, vesicle transport assay, molecular docking, ELISA for cGAMP, RNA transcriptomics, ABCC10 overexpression and silencing, in vivo tumor radiotherapy + nilotinib combination","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — vesicle transport and docking identify R545 binding site, functional pathway suppression confirmed by overexpression/silencing, single lab with multiple orthogonal methods","pmids":["40770563"],"is_preprint":false},{"year":2025,"finding":"BRG1 (SMARCA4)-containing SWI/SNF chromatin remodeling complex enables transcription of ABCC10 (along with ABCC3 and ABCC5); pharmacological inhibition (PFI3) or PROTAC degradation (ACBI1) of SWI/SNF, or BRG1 siRNA silencing, substantially reduces ABCC10 transcription and reverses lysosomal drug sequestration in paclitaxel-resistant cancer cells.","method":"SMARCA4 siRNA knockdown, PFI3/ACBI1 pharmacological SWI/SNF inhibition, ABCC10 gene expression, lysosomal drug distribution in paclitaxel-resistant TNBC and NSCLC cells","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with two orthogonal methods (genetic and pharmacological) with functional readout; preprint, not yet peer reviewed","pmids":[],"is_preprint":true}],"current_model":"ABCC10/MRP7 is a 171 kDa, three-transmembrane-domain ABC efflux transporter localized to the basolateral plasma membrane (and redistributed to lysosomes in drug-resistant cells) that uses ATP hydrolysis to transport amphipathic anions including E2 17βG, LTC4, tamoxifen, and cGAMP, as well as a broad range of anticancer drugs (taxanes, vinca alkaloids, epothilone B, nucleoside analogues, gefitinib, oxaliplatin), thereby conferring multidrug resistance; its transcription is driven by FOXM1 (direct promoter binding) and BRG1/SWI/SNF, and its expression is regulated post-transcriptionally by m6A modification (FTO/YTHDF2 axis) and by miR-let-7g/i targeting its 3'UTR; in vivo knockout studies confirm it as an endogenous determinant of taxane sensitivity, fat absorption, and radiotherapy resistance through cGAMP efflux and STING pathway suppression."},"narrative":{"mechanistic_narrative":"ABCC10/MRP7 is an ATP-dependent ABC efflux transporter that exports amphipathic anions and a broad spectrum of xenobiotics, thereby acting as an endogenous determinant of multidrug resistance [PMID:15256465, PMID:21576088]. It is a 1492-residue protein with three membrane-spanning domains architecturally resembling other MRP family members [PMID:11146224], and it catalyzes MgATP-dependent transport of the model amphipathic anion E2 17βG with LTC4 as a potent competitive inhibitor; unlike MRP1/2, its transport activity is glutathione-independent [PMID:12527806, PMID:19118001]. Substrate engagement (E2 17βG, LTC4, tamoxifen, taxanes, Ara-C) stimulates its BeFx-sensitive ATPase activity, and in polarized epithelia it localizes to the basolateral surface and exports docetaxel vectorially from the apical to basolateral side [PMID:23087055]. Through this pump activity ABCC10 confers resistance to taxanes, vinca alkaloids, epothilone B, nucleoside analogues, and the kinase inhibitor gefitinib by reducing intracellular drug accumulation [PMID:15256465, PMID:19118001, PMID:30515095], and it additionally effluxes antiretroviral agents such as tenofovir and nevirapine [PMID:21628669, PMID:22082652]. Knockout mouse studies establish its in vivo roles: Abcc10-null animals are hypersensitive to taxanes and exhibit altered tumor growth and metastasis [PMID:21576088, PMID:24937672], and ABCC10 also governs dietary fat absorption, with its deletion reducing intestinal triglyceride uptake and protecting against diet-induced obesity [PMID:36430292]. More recently ABCC10 was shown to bind and efflux the STING agonist 2'3'-cGAMP at the R545 site, suppressing STING-TBK1-IRF3 signaling and conferring radiotherapy resistance [PMID:40770563]. Its expression is controlled transcriptionally by FOXM1, which binds the ABCC10 promoter directly to drive 5-FU resistance [PMID:28051999], by the BRG1/SWI/SNF chromatin-remodeling complex, and post-transcriptionally via the FTO/YTHDF2 m6A axis [PMID:33563765]. In drug-resistant cells the transporter redistributes from the plasma membrane to lysosomes, where it contributes to intracellular drug sequestration [PMID:37767694].","teleology":[{"year":2001,"claim":"Established the basic molecular identity of ABCC10/MRP7 as a multidomain ABC transporter, providing the structural framework for all subsequent functional work.","evidence":"cDNA sequence analysis with in vitro translation in reticulocyte lysates and FISH chromosomal mapping","pmids":["11146224"],"confidence":"Medium","gaps":["No transport substrate or function demonstrated","No experimental membrane topology validation","Protein product confirmed only in vitro, not in cells"]},{"year":2003,"claim":"Answered whether ABCC10 is a functional transporter by demonstrating MgATP-dependent transport of an amphipathic anion, defining its biochemical activity class.","evidence":"Membrane vesicle transport assays with kinetic and competitive inhibition analysis in transfected HEK293 cells","pmids":["12527806"],"confidence":"High","gaps":["Physiological substrate unknown","Only modest LTC4 transport, scope of endogenous cargo undefined","No link to drug resistance yet"]},{"year":2004,"claim":"Connected ABCC10 transport activity to clinical drug resistance by showing it effluxes taxanes and vinca alkaloids, establishing it as a multidrug resistance transporter.","evidence":"Ectopic overexpression in HEK293 cells with cytotoxicity and radiolabeled paclitaxel accumulation assays","pmids":["15256465"],"confidence":"High","gaps":["Overexpression context only, endogenous relevance not shown","Direct transport of taxanes in vesicles not measured here","No in vivo confirmation"]},{"year":2009,"claim":"Expanded the substrate range to nucleoside analogues and epothilone B and distinguished ABCC10 mechanistically from MRP1/2 by showing glutathione-independent transport.","evidence":"Transfected HEK293 cells and P-gp/Mrp1-deficient MEFs with cytotoxicity, accumulation, and BSO experiments","pmids":["19118001"],"confidence":"High","gaps":["Co-substrate requirements (if any) not fully defined","Endogenous expression context still not addressed"]},{"year":2008,"claim":"Demonstrated that endogenously expressed ABCC10 drives paclitaxel efflux in lung cancer cells, moving beyond overexpression artifacts.","evidence":"siRNA knockdown and sulfinpyrazone inhibition in NSCLC cells with intracellular paclitaxel accumulation","pmids":["18445659"],"confidence":"Medium","gaps":["Single cancer cell type","No in vivo validation in this study"]},{"year":2009,"claim":"Identified kinase inhibitors (EGFR and BCR-Abl TKIs) as functional reversal agents that inhibit ABCC10 efflux without altering its expression, defining a pharmacological resensitization strategy.","evidence":"Accumulation/efflux assays and Western blot in MRP7-transfected HEK293 cells","pmids":["19720054","19841739"],"confidence":"Medium","gaps":["Binding site of inhibitors not mapped","Clinical translatability not tested","Single-lab observations"]},{"year":2008,"claim":"Characterized cepharanthine as a competitive ABCC10 inhibitor with defined kinetics, providing a chemical tool for dissecting transport function.","evidence":"Membrane vesicle E2 17βG competitive inhibition and paclitaxel accumulation assays in transfected cells","pmids":["19150344"],"confidence":"Medium","gaps":["Specificity across other ABC transporters not established","No structural basis for inhibition"]},{"year":2011,"claim":"Provided the first in vivo genetic proof that Abcc10 is an endogenous determinant of taxane sensitivity and host toxicity.","evidence":"Abcc10-knockout mice and MEFs with in vivo paclitaxel treatment and pathological assessment","pmids":["21576088"],"confidence":"High","gaps":["Tissue distribution of effect not fully mapped","Mechanism of bone marrow toxicity not dissected"]},{"year":2012,"claim":"Integrated ATPase reconstitution, vectorial transport, and basolateral localization, and added tamoxifen as a substrate, establishing the polarized export directionality of ABCC10.","evidence":"Crude membrane BeFx-sensitive ATPase assays and transepithelial docetaxel transport in polarized LLC-PK1 cells","pmids":["23087055"],"confidence":"High","gaps":["Coupling stoichiometry of ATP hydrolysis to transport not quantified","Structural basis of substrate binding unknown"]},{"year":2011,"claim":"Showed ABCC10 effluxes antiretroviral drugs in immune cells, extending its pharmacological relevance to HIV therapy.","evidence":"Overexpression, cepharanthine inhibition, and siRNA knockdown in CD4+ cells and macrophages with accumulation assays for tenofovir and nevirapine","pmids":["21628669","22082652"],"confidence":"Medium","gaps":["Direct vesicle transport of these drugs not measured","Clinical pharmacokinetic impact not established"]},{"year":2014,"claim":"Revealed an in vivo role beyond chemoresistance, linking Abcc10 to mammary tumor growth, apoptosis, and metastasis.","evidence":"Abcc10-null x MMTV-PyVmT mouse cross with allograft, migration, and docetaxel survival assays","pmids":["24937672"],"confidence":"Medium","gaps":["Transported effector responsible for growth/metastasis phenotype not identified","Mechanism linking efflux to apoptosis unclear"]},{"year":2017,"claim":"Identified FOXM1 as a direct transcriptional driver of ABCC10, providing an upstream regulatory mechanism for resistance.","evidence":"ChIP for promoter binding, FOXM1 gain/loss-of-function, and ABCC10-inhibitor xenografts in colorectal cancer","pmids":["28051999"],"confidence":"Medium","gaps":["Other transcriptional regulators not addressed here","Single lab"]},{"year":2018,"claim":"Defined gefitinib as an actively effluxed substrate, implicating ABCC10 in resistance to targeted EGFR therapy.","evidence":"In vitro transport assay with efflux ratio, overexpression, and xenografts in NSCLC","pmids":["30515095"],"confidence":"Medium","gaps":["Endogenous loss-of-function not tested in this study","Kinetics of gefitinib transport not measured"]},{"year":2021,"claim":"Established post-transcriptional control of ABCC10 by the m6A machinery, showing FTO-mediated demethylation stabilizes ABCC10 mRNA to transfer drug resistance.","evidence":"Exosome internalization assays, m6A quantification, FTO and YTHDF2 manipulation, in vitro and in vivo resistance models","pmids":["33563765"],"confidence":"Medium","gaps":["Specific m6A sites on ABCC10 mRNA not exhaustively mapped","Single lab"]},{"year":2022,"claim":"Uncovered a physiological metabolic role by showing Abcc10 governs dietary fat absorption and influences diet-induced obesity.","evidence":"Abcc10-knockout mice with plasma/intestinal lipid measurements and fat absorption assays","pmids":["36430292"],"confidence":"Medium","gaps":["Direct lipid substrate transported by ABCC10 not identified","Molecular link between efflux and enterocyte fatty acid uptake unclear"]},{"year":2023,"claim":"Revealed that ABCC10 redistributes to lysosomes in resistant cells, contributing to intracellular drug sequestration as an alternative resistance mode.","evidence":"Confocal localization, siRNA knockdown, and flow cytometry for lysosomal drug accumulation in paclitaxel-resistant TNBC and NSCLC cells","pmids":["37767694"],"confidence":"Medium","gaps":["Trafficking signals driving lysosomal relocalization unknown","Relative contribution vs plasma membrane efflux unquantified"]},{"year":2025,"claim":"Defined a novel immunomodulatory function by showing ABCC10 effluxes cGAMP at the R545 site to suppress STING signaling and confer radiotherapy resistance.","evidence":"CRISPR metabolic screen, vesicle transport, docking, ELISA, transcriptomics, and in vivo radiotherapy + nilotinib combination","pmids":["40770563"],"confidence":"Medium","gaps":["R545 binding site predicted by docking, not structurally resolved","Single lab","Generality across tumor types not established"]},{"year":2025,"claim":"Implicated the BRG1/SWI/SNF chromatin-remodeling complex in enabling ABCC10 transcription and lysosomal drug sequestration.","evidence":"SMARCA4 siRNA, PFI3/ACBI1 SWI/SNF inhibition, and lysosomal drug distribution in resistant cancer cells (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint, not yet peer reviewed","Direct SWI/SNF occupancy at ABCC10 locus vs indirect effect not distinguished"]},{"year":null,"claim":"An experimentally determined structure of ABCC10 and direct validation of its substrate/inhibitor binding sites remain unresolved, limiting mechanistic understanding of how its broad substrate range maps onto the transport cycle.","evidence":"","pmids":[],"confidence":"Low","gaps":["No experimental cryo-EM/crystal structure (only an MRP1-based homology model exists)","Coupling of ATP hydrolysis to transport not quantified","How a single pump accommodates such chemically diverse substrates unexplained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[1,5]},{"term_id":"GO:0005215","term_label":"transporter activity","supporting_discovery_ids":[1,2,3,5,13,21]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[1,5]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5,18]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[18]}],"pathway":[{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[1,5,10,11,20]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,3,4,13,21]},{"term_id":"R-HSA-9748784","term_label":"Drug ADME","supporting_discovery_ids":[10,11,13]}],"complexes":[],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5T3U5","full_name":"ATP-binding cassette sub-family C member 10","aliases":["Multidrug resistance-associated protein 7"],"length_aa":1492,"mass_kda":161.6,"function":"ATP-dependent transporter of the ATP-binding cassette (ABC) family that actively extrudes physiological compounds, and xenobiotics from cells. Lipophilic anion transporter that mediates ATP-dependent transport of glucuronide conjugates such as estradiol-17-beta-o-glucuronide and GSH conjugates such as leukotriene C4 (LTC4) (PubMed:12527806, PubMed:15256465). May regulate the transport of organic compounds in testes across the blood-testis-barrier (Probable). Mediates intercellular propagation of antiviral immune signaling in early stages of infection (By similarity). In RNA virus-infected cells, oligoadenylate synthase senses viral dsRNA and generates 2',5'-oligoadenylates (2-5A) which act as second messengers to activate RNASEL and type I interferon signaling to inhibit viral replication (By similarity). This innate signaling pathway is locally extended and amplified by ABCC10, which exports 2-5A from virus-infected cells to cross-activates RNASEL in uninfected neighboring cells and confers protection against viral infection (By similarity). Mediates multidrug resistance (MDR) in cancer cells by preventing the intracellular accumulation of certain antitumor drugs, such as, docetaxel and paclitaxel (PubMed:15256465, PubMed:23087055). Does not transport glycocholic acid, taurocholic acid, MTX, folic acid, cAMP, or cGMP (PubMed:12527806)","subcellular_location":"Cell membrane; Basolateral cell membrane; Basal cell membrane","url":"https://www.uniprot.org/uniprotkb/Q5T3U5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ABCC10","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ABCC10","total_profiled":1310},"omim":[{"mim_id":"618513","title":"LEBER CONGENITAL AMAUROSIS 19; LCA19","url":"https://www.omim.org/entry/618513"},{"mim_id":"618439","title":"UBIQUITIN-SPECIFIC PROTEASE 45; USP45","url":"https://www.omim.org/entry/618439"},{"mim_id":"612509","title":"ATP-BINDING CASSETTE, SUBFAMILY C, MEMBER 10; ABCC10","url":"https://www.omim.org/entry/612509"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in 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lysate in vitro translation, fluorescence in situ hybridization\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 (in vitro translation confirming protein product) / Weak — single lab, foundational structural characterization\",\n      \"pmids\": [\"11146224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"ABCC10/MRP7 mediates MgATP-dependent transport of the amphipathic anion 17β-estradiol-17β-D-glucuronide (E2 17βG) with Km ~57.8 µM and Vmax ~53.1 pmol/mg/min in membrane vesicles; LTC4 is a potent competitive inhibitor (Ki ~1.5 µM), and the pump shows modest LTC4 transport but not other canonical MRP substrates tested.\",\n      \"method\": \"Membrane vesicle transport assay using HEK293 cells transfected with MRP7 expression vector; competitive inhibition kinetics\",\n      \"journal\": \"Molecular pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstituted vesicle transport with kinetic parameters, single lab but multiple substrates and inhibitors tested rigorously\",\n      \"pmids\": [\"12527806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"ABCC10/MRP7 overexpression in HEK293 cells confers resistance to docetaxel (9–13-fold), paclitaxel (3-fold), vincristine (3-fold), and vinblastine (3–4-fold); MRP7-transfected cells show reduced accumulation of radiolabeled paclitaxel, consistent with ATP-dependent efflux pump activity.\",\n      \"method\": \"Ectopic expression in HEK293 cells, cytotoxicity assays, radiolabeled drug accumulation assay\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean overexpression with defined phenotypic readout and accumulation assay; independently replicated across multiple subsequent studies\",\n      \"pmids\": [\"15256465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ABCC10/MRP7 confers resistance to nucleoside analogues (cytarabine/Ara-C, gemcitabine, 2',3'-dideoxycytidine, PMEA) and epothilone B in addition to taxanes and vinca alkaloids; buthionine sulfoximine did not attenuate MRP7-conferred resistance, indicating MRP7-mediated transport does not involve glutathione (unlike MRP1/2).\",\n      \"method\": \"MRP7-transfected HEK293 cells and mouse embryo fibroblasts deficient in P-gp and Mrp1; cytotoxicity and radiolabeled drug accumulation assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple drug classes tested in two independent cellular backgrounds with accumulation assays; glutathione-independence confirmed by BSO experiment\",\n      \"pmids\": [\"19118001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Abcc10 knockout mice show that Abcc10 is an endogenous resistance factor in vivo: Abcc10−/− mouse embryo fibroblasts are hypersensitive to docetaxel, paclitaxel, vincristine, and Ara-C with increased drug accumulation; Abcc10−/− mice treated with paclitaxel exhibit increased lethality with neutropenia and bone marrow/spleen/thymus toxicity.\",\n      \"method\": \"Abcc10−/− mouse generation, MEF cytotoxicity/accumulation assays, in vivo paclitaxel treatment with pathological assessment\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout mouse model with in vivo and in vitro phenotypic readouts, first demonstration of in vivo relevance\",\n      \"pmids\": [\"21576088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ABCC10 substrates E2 17βG and LTC4 stimulate ABCC10 BeFx-sensitive ATPase activity; tamoxifen is identified as a novel substrate and ATPase stimulator; docetaxel, paclitaxel, and Ara-C also increase basal ATPase activity. ABCC10 localizes to the basolateral cell surface and exports docetaxel from apical to basolateral side in transepithelial LLC-PK1 assays. Sorafenib and cepharanthine inhibit ABCC10 docetaxel transport activity.\",\n      \"method\": \"Crude membrane ATPase assays with BeFx (vanadate-sensitive controls), transepithelial well assay in ABCC10-overexpressing LLC-PK1 cells, radiolabeled docetaxel transport\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biochemical ATPase reconstitution, vectorial transport in polarized cells, and subcellular localization all in one study with functional consequence\",\n      \"pmids\": [\"23087055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Sulfinpyrazone (an ABCC10 inhibitor) alters sensitivity to paclitaxel in ABCC10-expressing NSCLC cells concomitant with increased intracellular paclitaxel accumulation; siRNA knockdown of ABCC10 enhances paclitaxel cytotoxicity in NCI-H23 cells with increased intracellular paclitaxel, confirming ABCC10 effluxes paclitaxel endogenously in lung cancer cells.\",\n      \"method\": \"siRNA knockdown in NSCLC cells, pharmacological inhibition with sulfinpyrazone, intracellular paclitaxel accumulation assay\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function (siRNA) and pharmacological inhibition with accumulation readout in endogenous cancer cell context\",\n      \"pmids\": [\"18445659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Lapatinib and erlotinib (EGFR TKIs) reverse MRP7/ABCC10-mediated multidrug resistance by inhibiting drug efflux function (increased intracellular [3H]-paclitaxel accumulation and decreased efflux in MRP7-transfected cells) without altering MRP7 protein expression levels.\",\n      \"method\": \"MRP7-transfected HEK293 cells, cytotoxicity assay, [3H]-paclitaxel accumulation and efflux assays, Western blot\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, accumulation/efflux assays demonstrate functional inhibition mechanism\",\n      \"pmids\": [\"19720054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Imatinib and nilotinib (BCR-Abl TKIs) reverse MRP7/ABCC10-mediated multidrug resistance by inhibiting paclitaxel efflux and increasing intracellular [3H]-paclitaxel accumulation in MRP7-transfected HEK293 cells, without altering MRP7 expression.\",\n      \"method\": \"MRP7-transfected HEK293 cells, MTT assay, [3H]-paclitaxel accumulation and efflux assays, Western blot\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, accumulation/efflux assays demonstrate functional inhibition of MRP7 transport activity\",\n      \"pmids\": [\"19841739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Cepharanthine reverses MRP7/ABCC10-mediated paclitaxel resistance and competitively inhibits E2 17βG transport by MRP7 in membrane vesicle assays with a Ki of 4.86 µM, identifying it as a competitive inhibitor of ABCC10.\",\n      \"method\": \"MRP7-transfected HEK293 cells, paclitaxel accumulation/efflux assays, membrane vesicle E2 17βG transport competitive inhibition assay\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro vesicle transport with kinetic inhibition constants, single lab\",\n      \"pmids\": [\"19150344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Tenofovir (TFV) is a substrate for ABCC10: TFV accumulation is 35% lower in HEK293-ABCC10 cells than parental HEK293 cells, reversed by cepharanthine; siRNA knockdown of ABCC10 increases TFV accumulation in CD4+ cells (18%) and monocyte-derived macrophages (25%).\",\n      \"method\": \"ABCC10-transfected HEK293 cells, pharmacological inhibition with cepharanthine, siRNA knockdown in primary CD4+ cells and macrophages, drug accumulation assay\",\n      \"journal\": \"The Journal of infectious diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression and loss-of-function (siRNA) in two cell types with accumulation readout, pharmacological confirmation\",\n      \"pmids\": [\"21628669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Nevirapine is a substrate for ABCC10: accumulation is 37% lower in HEK293-ABCC10 cells vs. parental, reversed by cepharanthine; siRNA knockdown increases nevirapine accumulation in CD4+ cells (32%) and monocyte-derived macrophages (38%).\",\n      \"method\": \"ABCC10-transfected HEK293 cells, siRNA knockdown in CD4+ cells and macrophages, drug accumulation assays, pharmacological inhibition\",\n      \"journal\": \"Pharmacogenetics and genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression and loss-of-function in primary cells with accumulation readout and pharmacological confirmation\",\n      \"pmids\": [\"22082652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"FOXM1 promotes 5-FU resistance in colorectal cancer by directly binding to the ABCC10 promoter and driving its transcription; ABCC10 inhibition reverses FOXM1-induced 5-FU resistance in vivo.\",\n      \"method\": \"Chromatin immunoprecipitation (promoter binding), FOXM1 overexpression and silencing in CRC cells, in vivo xenograft with ABCC10 inhibitor\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding demonstrated, functional rescue in vivo, single lab\",\n      \"pmids\": [\"28051999\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ABCC10 actively effluxes gefitinib with an efflux ratio of 7.8 in an in vitro transport assay; overexpression of ABCC10 reduces intracellular gefitinib accumulation and decreases gefitinib sensitivity in NSCLC cells and xenograft models.\",\n      \"method\": \"In vitro transport assay, ABCC10-overexpressing cell lines, intracellular gefitinib accumulation measurement, in vivo xenograft\",\n      \"journal\": \"Frontiers in pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transport assay with defined efflux ratio, overexpression in vitro and in vivo, single lab\",\n      \"pmids\": [\"30515095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Exosomal delivery of the m6A demethylase FTO from gefitinib-resistant cells to recipient cells decreases m6A modification on ABCC10 mRNA, reducing YTHDF2-mediated decay and thereby increasing ABCC10 expression, which mediates gefitinib resistance transfer.\",\n      \"method\": \"Exosome internalization assays, m6A quantification, FTO knockdown/overexpression, YTHDF2 functional studies, in vitro and in vivo resistance models\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (m6A sequencing, FTO KD, YTHDF2 pathway), single lab, functional in vivo validation\",\n      \"pmids\": [\"33563765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Abcc10 loss in MMTV-PyVmT mammary tumor mice results in faster tumor growth with reduced apoptosis and reduced metastasis; Abcc10-null tumor-derived cell lines are less migratory; Abcc10−/− mice show increased survival upon docetaxel treatment, confirming in vivo role as docetaxel resistance factor in mammary tumors.\",\n      \"method\": \"Abcc10−/− x MMTV-PyVmT mouse cross, allograft and cellular assays, migration assays, in vivo docetaxel treatment survival analysis\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO in relevant tumor model with multiple cellular and in vivo readouts, single lab\",\n      \"pmids\": [\"24937672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ABCC10 homology model (based on cryo-EM structure of MRP1) combined with molecular dynamics simulations and docking identifies predicted substrate- and modulator-binding sites within the transmembrane region of MRP7/ABCC10, with motion patterns consistent with the ABC efflux mechanism.\",\n      \"method\": \"Homology modeling based on MRP1 cryo-EM structure, molecular dynamics simulation, in silico docking\",\n      \"journal\": \"MedComm\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational modeling only, no experimental structural validation of binding sites\",\n      \"pmids\": [\"34766143\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LXRα activation by its agonist TO901317 alters ABCC10 gene expression in rat hepatic and cardiac tissues, identifying ABCC10 as a specific LXRα target gene.\",\n      \"method\": \"In vivo rat hypercholesterolemia model, LXRα agonist treatment, hepatic/cardiac gene expression analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, gene expression readout without direct promoter binding or mechanistic follow-up\",\n      \"pmids\": [\"35462094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ABCC10 redistributes from plasma membrane to lysosomes in paclitaxel-resistant cancer cells; lysosome-localized ABCC10 (along with ABCC3 and ABCC5) contributes to sequestration of doxorubicin and paclitaxel-OregonGreen488 in lysosomes; siRNA silencing of ABCC10 limits lysosomal drug accumulation.\",\n      \"method\": \"Western blot and confocal microscopy for localization, siRNA knockdown, ABCC inhibitors, flow cytometry for drug accumulation in lysosomes in paclitaxel-resistant TNBC and NSCLC cells\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — localization tied to functional drug sequestration outcome, loss-of-function confirmation, single lab\",\n      \"pmids\": [\"37767694\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ABCC10 regulates glucosylceramide (GlcCer) synthesis and efflux differentially: sorafenib (ABCC10 inhibitor) decreases both GlcCer synthesis and efflux, while cepharanthine reduces only GlcCer efflux but not synthesis, in Huh-7 liver cells.\",\n      \"method\": \"Pharmacological inhibition with sorafenib and cepharanthine, GlcCer synthesis and efflux measurement in Huh-7 cells\",\n      \"journal\": \"Nutrients\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pharmacological inhibition only (no genetic KO/KD confirmation), single lab, mechanistic interpretation indirect\",\n      \"pmids\": [\"36678216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ABCC10 deletion in mice results in lower plasma and intestinal triglycerides (~38% and 36% reduction), ameliorates diet-induced obesity, reduces oleate uptake by enterocytes (~25–30%), and reduces intestinal triglyceride absorption (~37%), indicating ABCC10 regulates dietary fat absorption.\",\n      \"method\": \"Abcc10 knockout mice, plasma/intestinal lipid measurements, insulin/glucose tolerance tests, intestinal fat absorption assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO mouse model with multiple metabolic readouts, single lab\",\n      \"pmids\": [\"36430292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ABCC10 binds and effluxes 2'3'-cyclic GMP-AMP (cGAMP) in an ATP-dependent manner at the R545 site; ABCC10-mediated cGAMP export suppresses the STING-TBK1-IRF3 signaling pathway, reducing RT-induced ROS and DNA damage, thereby conferring radiotherapy resistance. Nilotinib (ABCC10 inhibitor) combined with radiotherapy synergistically inhibits tumor growth in vivo.\",\n      \"method\": \"CRISPR metabolic library screen, vesicle transport assay, molecular docking, ELISA for cGAMP, RNA transcriptomics, ABCC10 overexpression and silencing, in vivo tumor radiotherapy + nilotinib combination\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — vesicle transport and docking identify R545 binding site, functional pathway suppression confirmed by overexpression/silencing, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"40770563\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"BRG1 (SMARCA4)-containing SWI/SNF chromatin remodeling complex enables transcription of ABCC10 (along with ABCC3 and ABCC5); pharmacological inhibition (PFI3) or PROTAC degradation (ACBI1) of SWI/SNF, or BRG1 siRNA silencing, substantially reduces ABCC10 transcription and reverses lysosomal drug sequestration in paclitaxel-resistant cancer cells.\",\n      \"method\": \"SMARCA4 siRNA knockdown, PFI3/ACBI1 pharmacological SWI/SNF inhibition, ABCC10 gene expression, lysosomal drug distribution in paclitaxel-resistant TNBC and NSCLC cells\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with two orthogonal methods (genetic and pharmacological) with functional readout; preprint, not yet peer reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"ABCC10/MRP7 is a 171 kDa, three-transmembrane-domain ABC efflux transporter localized to the basolateral plasma membrane (and redistributed to lysosomes in drug-resistant cells) that uses ATP hydrolysis to transport amphipathic anions including E2 17βG, LTC4, tamoxifen, and cGAMP, as well as a broad range of anticancer drugs (taxanes, vinca alkaloids, epothilone B, nucleoside analogues, gefitinib, oxaliplatin), thereby conferring multidrug resistance; its transcription is driven by FOXM1 (direct promoter binding) and BRG1/SWI/SNF, and its expression is regulated post-transcriptionally by m6A modification (FTO/YTHDF2 axis) and by miR-let-7g/i targeting its 3'UTR; in vivo knockout studies confirm it as an endogenous determinant of taxane sensitivity, fat absorption, and radiotherapy resistance through cGAMP efflux and STING pathway suppression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ABCC10/MRP7 is an ATP-dependent ABC efflux transporter that exports amphipathic anions and a broad spectrum of xenobiotics, thereby acting as an endogenous determinant of multidrug resistance [#2, #4]. It is a 1492-residue protein with three membrane-spanning domains architecturally resembling other MRP family members [#0], and it catalyzes MgATP-dependent transport of the model amphipathic anion E2 17\\u03b2G with LTC4 as a potent competitive inhibitor; unlike MRP1/2, its transport activity is glutathione-independent [#1, #3]. Substrate engagement (E2 17\\u03b2G, LTC4, tamoxifen, taxanes, Ara-C) stimulates its BeFx-sensitive ATPase activity, and in polarized epithelia it localizes to the basolateral surface and exports docetaxel vectorially from the apical to basolateral side [#5]. Through this pump activity ABCC10 confers resistance to taxanes, vinca alkaloids, epothilone B, nucleoside analogues, and the kinase inhibitor gefitinib by reducing intracellular drug accumulation [#2, #3, #13], and it additionally effluxes antiretroviral agents such as tenofovir and nevirapine [#10, #11]. Knockout mouse studies establish its in vivo roles: Abcc10-null animals are hypersensitive to taxanes and exhibit altered tumor growth and metastasis [#4, #15], and ABCC10 also governs dietary fat absorption, with its deletion reducing intestinal triglyceride uptake and protecting against diet-induced obesity [#20]. More recently ABCC10 was shown to bind and efflux the STING agonist 2'3'-cGAMP at the R545 site, suppressing STING-TBK1-IRF3 signaling and conferring radiotherapy resistance [#21]. Its expression is controlled transcriptionally by FOXM1, which binds the ABCC10 promoter directly to drive 5-FU resistance [#12], by the BRG1/SWI/SNF chromatin-remodeling complex [#22], and post-transcriptionally via the FTO/YTHDF2 m6A axis [#14]. In drug-resistant cells the transporter redistributes from the plasma membrane to lysosomes, where it contributes to intracellular drug sequestration [#18].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Established the basic molecular identity of ABCC10/MRP7 as a multidomain ABC transporter, providing the structural framework for all subsequent functional work.\",\n      \"evidence\": \"cDNA sequence analysis with in vitro translation in reticulocyte lysates and FISH chromosomal mapping\",\n      \"pmids\": [\"11146224\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No transport substrate or function demonstrated\", \"No experimental membrane topology validation\", \"Protein product confirmed only in vitro, not in cells\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Answered whether ABCC10 is a functional transporter by demonstrating MgATP-dependent transport of an amphipathic anion, defining its biochemical activity class.\",\n      \"evidence\": \"Membrane vesicle transport assays with kinetic and competitive inhibition analysis in transfected HEK293 cells\",\n      \"pmids\": [\"12527806\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological substrate unknown\", \"Only modest LTC4 transport, scope of endogenous cargo undefined\", \"No link to drug resistance yet\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Connected ABCC10 transport activity to clinical drug resistance by showing it effluxes taxanes and vinca alkaloids, establishing it as a multidrug resistance transporter.\",\n      \"evidence\": \"Ectopic overexpression in HEK293 cells with cytotoxicity and radiolabeled paclitaxel accumulation assays\",\n      \"pmids\": [\"15256465\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Overexpression context only, endogenous relevance not shown\", \"Direct transport of taxanes in vesicles not measured here\", \"No in vivo confirmation\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Expanded the substrate range to nucleoside analogues and epothilone B and distinguished ABCC10 mechanistically from MRP1/2 by showing glutathione-independent transport.\",\n      \"evidence\": \"Transfected HEK293 cells and P-gp/Mrp1-deficient MEFs with cytotoxicity, accumulation, and BSO experiments\",\n      \"pmids\": [\"19118001\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Co-substrate requirements (if any) not fully defined\", \"Endogenous expression context still not addressed\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated that endogenously expressed ABCC10 drives paclitaxel efflux in lung cancer cells, moving beyond overexpression artifacts.\",\n      \"evidence\": \"siRNA knockdown and sulfinpyrazone inhibition in NSCLC cells with intracellular paclitaxel accumulation\",\n      \"pmids\": [\"18445659\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single cancer cell type\", \"No in vivo validation in this study\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified kinase inhibitors (EGFR and BCR-Abl TKIs) as functional reversal agents that inhibit ABCC10 efflux without altering its expression, defining a pharmacological resensitization strategy.\",\n      \"evidence\": \"Accumulation/efflux assays and Western blot in MRP7-transfected HEK293 cells\",\n      \"pmids\": [\"19720054\", \"19841739\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding site of inhibitors not mapped\", \"Clinical translatability not tested\", \"Single-lab observations\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Characterized cepharanthine as a competitive ABCC10 inhibitor with defined kinetics, providing a chemical tool for dissecting transport function.\",\n      \"evidence\": \"Membrane vesicle E2 17\\u03b2G competitive inhibition and paclitaxel accumulation assays in transfected cells\",\n      \"pmids\": [\"19150344\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specificity across other ABC transporters not established\", \"No structural basis for inhibition\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Provided the first in vivo genetic proof that Abcc10 is an endogenous determinant of taxane sensitivity and host toxicity.\",\n      \"evidence\": \"Abcc10-knockout mice and MEFs with in vivo paclitaxel treatment and pathological assessment\",\n      \"pmids\": [\"21576088\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue distribution of effect not fully mapped\", \"Mechanism of bone marrow toxicity not dissected\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Integrated ATPase reconstitution, vectorial transport, and basolateral localization, and added tamoxifen as a substrate, establishing the polarized export directionality of ABCC10.\",\n      \"evidence\": \"Crude membrane BeFx-sensitive ATPase assays and transepithelial docetaxel transport in polarized LLC-PK1 cells\",\n      \"pmids\": [\"23087055\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Coupling stoichiometry of ATP hydrolysis to transport not quantified\", \"Structural basis of substrate binding unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed ABCC10 effluxes antiretroviral drugs in immune cells, extending its pharmacological relevance to HIV therapy.\",\n      \"evidence\": \"Overexpression, cepharanthine inhibition, and siRNA knockdown in CD4+ cells and macrophages with accumulation assays for tenofovir and nevirapine\",\n      \"pmids\": [\"21628669\", \"22082652\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vesicle transport of these drugs not measured\", \"Clinical pharmacokinetic impact not established\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Revealed an in vivo role beyond chemoresistance, linking Abcc10 to mammary tumor growth, apoptosis, and metastasis.\",\n      \"evidence\": \"Abcc10-null x MMTV-PyVmT mouse cross with allograft, migration, and docetaxel survival assays\",\n      \"pmids\": [\"24937672\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transported effector responsible for growth/metastasis phenotype not identified\", \"Mechanism linking efflux to apoptosis unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified FOXM1 as a direct transcriptional driver of ABCC10, providing an upstream regulatory mechanism for resistance.\",\n      \"evidence\": \"ChIP for promoter binding, FOXM1 gain/loss-of-function, and ABCC10-inhibitor xenografts in colorectal cancer\",\n      \"pmids\": [\"28051999\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Other transcriptional regulators not addressed here\", \"Single lab\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Defined gefitinib as an actively effluxed substrate, implicating ABCC10 in resistance to targeted EGFR therapy.\",\n      \"evidence\": \"In vitro transport assay with efflux ratio, overexpression, and xenografts in NSCLC\",\n      \"pmids\": [\"30515095\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous loss-of-function not tested in this study\", \"Kinetics of gefitinib transport not measured\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established post-transcriptional control of ABCC10 by the m6A machinery, showing FTO-mediated demethylation stabilizes ABCC10 mRNA to transfer drug resistance.\",\n      \"evidence\": \"Exosome internalization assays, m6A quantification, FTO and YTHDF2 manipulation, in vitro and in vivo resistance models\",\n      \"pmids\": [\"33563765\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Specific m6A sites on ABCC10 mRNA not exhaustively mapped\", \"Single lab\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Uncovered a physiological metabolic role by showing Abcc10 governs dietary fat absorption and influences diet-induced obesity.\",\n      \"evidence\": \"Abcc10-knockout mice with plasma/intestinal lipid measurements and fat absorption assays\",\n      \"pmids\": [\"36430292\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct lipid substrate transported by ABCC10 not identified\", \"Molecular link between efflux and enterocyte fatty acid uptake unclear\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed that ABCC10 redistributes to lysosomes in resistant cells, contributing to intracellular drug sequestration as an alternative resistance mode.\",\n      \"evidence\": \"Confocal localization, siRNA knockdown, and flow cytometry for lysosomal drug accumulation in paclitaxel-resistant TNBC and NSCLC cells\",\n      \"pmids\": [\"37767694\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Trafficking signals driving lysosomal relocalization unknown\", \"Relative contribution vs plasma membrane efflux unquantified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined a novel immunomodulatory function by showing ABCC10 effluxes cGAMP at the R545 site to suppress STING signaling and confer radiotherapy resistance.\",\n      \"evidence\": \"CRISPR metabolic screen, vesicle transport, docking, ELISA, transcriptomics, and in vivo radiotherapy + nilotinib combination\",\n      \"pmids\": [\"40770563\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"R545 binding site predicted by docking, not structurally resolved\", \"Single lab\", \"Generality across tumor types not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated the BRG1/SWI/SNF chromatin-remodeling complex in enabling ABCC10 transcription and lysosomal drug sequestration.\",\n      \"evidence\": \"SMARCA4 siRNA, PFI3/ACBI1 SWI/SNF inhibition, and lysosomal drug distribution in resistant cancer cells (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer reviewed\", \"Direct SWI/SNF occupancy at ABCC10 locus vs indirect effect not distinguished\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"An experimentally determined structure of ABCC10 and direct validation of its substrate/inhibitor binding sites remain unresolved, limiting mechanistic understanding of how its broad substrate range maps onto the transport cycle.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No experimental cryo-EM/crystal structure (only an MRP1-based homology model exists)\", \"Coupling of ATP hydrolysis to transport not quantified\", \"How a single pump accommodates such chemically diverse substrates unexplained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"GO:0005215\", \"supporting_discovery_ids\": [1, 2, 3, 5, 13, 21]},\n      {\"term_id\": \"GO:0042626\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [1, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 18]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-382551\", \"supporting_discovery_ids\": [1, 5, 10, 11, 20]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 3, 4, 13, 21]},\n      {\"term_id\": \"R-HSA-9748784\", \"supporting_discovery_ids\": [10, 11, 13]}\n    ],\n    \"complexes\": [],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}