{"gene":"ROS1","run_date":"2026-06-10T06:43:37","timeline":{"discoveries":[{"year":1986,"finding":"The human ROS1 oncogene (previously called MCF3) encodes a protein with homology to tyrosine-specific protein kinases, possesses a putative transmembrane domain N-terminal to the kinase domain, and likely arose from a normal human ROS1 gene by loss of a putative extracellular domain during gene transfer. The activated MCF3 form lacks gross rearrangements beyond loss of the extracellular domain.","method":"DNA-mediated gene transfer, tumorigenicity assay, structural analysis of cDNA","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — original characterization paper with DNA transfer, tumorigenicity assay, and structural analysis; single lab but multiple complementary methods","pmids":["3785223"],"is_preprint":false},{"year":1987,"finding":"ROS1 is expressed at high levels specifically in glioblastoma-derived cell lines (but not in other cell lines) without gene amplification, and a potentially activating mutation at the ROS1 locus was detected in one glioblastoma line, indicating cell-type-specific expression and susceptibility to activating mutation.","method":"Northern blot survey of 45 cell lines, Southern blot copy-number analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic survey across 45 cell lines with two orthogonal methods (expression and copy number); single lab","pmids":["2827175"],"is_preprint":false},{"year":1987,"finding":"The human ROS1 gene (formerly MCF3) maps to the distal half of chromosome 6q, a region frequently rearranged in malignant cells, suggesting involvement in diverse tumor types.","method":"Chromosomal mapping (somatic cell hybrid panel)","journal":"Oncogene research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single chromosomal mapping experiment; no functional validation","pmids":["3329713"],"is_preprint":false},{"year":1991,"finding":"During mouse development, c-ros1 is transiently expressed in the kidney, intestine, and lung coinciding with major morphogenetic events; in the kidney, expression is confined to ureter epithelial cells involved in inductive interactions with metanephric mesenchyme, implicating ROS1 as a receptor tyrosine kinase in mesenchymal–epithelial inductive interactions.","method":"RNase protection assay, in situ hybridization","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal in vivo localization methods (RNase protection + in situ hybridization) with cell-type resolution; single lab","pmids":["1718742"],"is_preprint":false},{"year":2012,"finding":"ROS1 gene fusions (with multiple partner genes) were identified in lung adenocarcinoma by integrated molecular screening; the resulting fusion proteins retain the ROS1 kinase domain and act as oncogenic drivers, defining a molecular subgroup of NSCLC.","method":"RT-PCR, fluorescence in situ hybridization (FISH), integrated histopathology-based screening in 1,529 lung cancers","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — large-scale systematic screen (n=1529) with orthogonal methods (RT-PCR + FISH) across multiple labs/institutions; independently replicated","pmids":["22327623"],"is_preprint":false},{"year":2013,"finding":"ROS1 chromosomal rearrangements create fusion proteins in which the ROS1 kinase domain becomes constitutively active and drives cellular proliferation; downstream signaling from ROS1 fusion proteins activates the Ras/Raf/MEK/ERK1/2 proliferation module, the PI3K cell survival pathway, and the Vav3 cell migration pathway.","method":"Review/synthesis of preclinical cell-based assays and in vivo models reported across multiple studies","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — synthesis of multiple independent cell-based experiments showing pathway activation; no single reconstitution experiment cited within the abstract","pmids":["23719267"],"is_preprint":false},{"year":2014,"finding":"ROS1 inhibition with crizotinib showed marked antitumor activity in ROS1-rearranged NSCLC patients (72% objective response rate), establishing ROS1 kinase activity as an oncogenic driver and therapeutic target in this cancer subgroup. Seven distinct ROS1 fusion partners were identified; no correlation was observed between fusion partner type and clinical response to crizotinib.","method":"Phase I expansion cohort clinical trial (n=50), next-generation sequencing and RT-PCR for fusion partner identification, pharmacokinetics assessment","journal":"The New England journal of medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — prospective clinical trial with multiple orthogonal molecular analyses; replicated across subsequent independent cohorts","pmids":["25264305"],"is_preprint":false},{"year":2014,"finding":"ROS1 kinase is activated by reductive stress downstream of GPX1 deficiency: loss of GPX1 leads to glutathione accumulation (reductive stress), which causes s-glutathiolation of the ROS1-associated phosphatase SHP-2, inhibiting SHP-2 and permitting ROS1 phosphorylation at activation site Y2274, thereby promoting vascular smooth muscle cell proliferation and pathological vascular remodeling. ROS1 inhibition with crizotinib abolished this proliferative effect without impairing endothelialization.","method":"Constitutive Gpx1 knockout mouse model, gene variant pair analysis in patient cohorts, genome-wide association meta-analysis, glutathiolation biochemistry, crizotinib pharmacological inhibition, in vivo vascular remodeling assay","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (genetic KO, biochemical glutathiolation assay, pharmacological inhibition, in vivo model, human cohort validation) in a single study; mechanistically rigorous","pmids":["25401476"],"is_preprint":false},{"year":2015,"finding":"Structural and molecular dynamics studies of the ROS1 kinase domain revealed distinct structural features distinguishing ROS1 from ALK that underlie differences in inhibitor selectivity. Cabozantinib and foretinib show striking selectivity for ROS1 over ALK. Cell-based resistance profiling demonstrated that ROS1-selective inhibitors retain efficacy against the CD74-ROS1(G2032R) solvent-front mutation whereas dual ROS1/ALK inhibitors (including crizotinib) are ineffective against this mutation.","method":"Molecular dynamics simulation, cell-based resistance profiling (Ba/F3 and patient-derived cell models), inhibitor selectivity assays across seven compounds","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — structural modeling validated by cell-based functional assays across multiple inhibitors and resistance mutants; single lab but multiple orthogonal approaches","pmids":["26372962"],"is_preprint":false},{"year":2016,"finding":"ROS1 fusion protein subcellular localization differs depending on the fusion partner: partners that retain transmembrane domains or dimerization domains influence whether ROS1 fusions localize to different subcellular compartments, suggesting that distinct fusions activate different substrates in vivo. Unlike ALK fusion proteins (activated by amino-terminal dimerization), several ROS1 fusion partners including CD74 apparently lack dimerization ability, leaving the mechanism of constitutive kinase activation for those fusions unknown.","method":"Literature synthesis, structural analysis of fusion protein domains","journal":"Future oncology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — inferred from domain analysis and literature review; no direct experimental validation of localization-dependent substrate differences in this paper","pmids":["27256160"],"is_preprint":false},{"year":2017,"finding":"ROS1 protein-tyrosine kinase fusion proteins signal downstream through the Ras/Raf/MEK/ERK1/2 cell proliferation module, the PI3K cell survival pathway, and the Vav3 cell migration pathway. Crizotinib forms a complex within the front cleft between the small and large lobes of an active ROS1 protein-kinase domain and is classified as a type I inhibitor.","method":"Review of cell-based signaling studies; structural classification of inhibitor binding mode","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — synthesis of multiple independent cell-based experiments and structural data; consistent with prior mechanistic reports","pmids":["28465216"],"is_preprint":false},{"year":2018,"finding":"Repotrectinib (TPX-0005), a macrocyclic TKI, is highly potent against ROS1 (including the solvent-front mutations G2032R and D2033N) and overcomes resistance to earlier-generation ROS1 inhibitors both in vitro and in vivo; confirmed responses were achieved in patients with ROS1 fusion-positive cancers that had relapsed on earlier-generation TKIs due to solvent-front substitution-mediated resistance.","method":"In vitro kinase assays, in vivo mouse models, phase I/II first-in-human clinical trial","journal":"Cancer discovery","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro assays plus in vivo models plus clinical proof-of-concept; multiple orthogonal methods confirming mechanistic basis of resistance overcome","pmids":["30093503"],"is_preprint":false},{"year":2018,"finding":"ROS1 inhibition is synthetically lethal with E-cadherin (CDH1) deficiency in breast cancer cells. ROS1 inhibitors (foretinib, crizotinib) induced mitotic abnormalities, multinucleation, defective cytokinesis, and aberrant p120 catenin phosphorylation and localization specifically in E-cadherin-defective cells. In vivo, ROS1 inhibitors produced profound antitumor effects in multiple models of E-cadherin-defective breast cancer.","method":"CRISPR/Cas9-engineered CDH1 mutations, large-scale genetic perturbation screens in molecularly diverse breast tumor cell lines, pharmacological inhibition (foretinib, crizotinib), immunofluorescence for mitotic phenotypes, p120 catenin localization assays, in vivo mouse tumor models","journal":"Cancer discovery","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR genetic engineering plus large-scale screens plus pharmacological validation plus in vivo models; mechanistically linked to cytokinesis defect and p120 catenin mislocalization; replicated across multiple cell lines","pmids":["29610289"],"is_preprint":false},{"year":2019,"finding":"DS-6051b, a selective ROS1/NTRK inhibitor, inhibits both wild-type ROS1 fusions and the crizotinib-resistant G2032R mutant ROS1 in vitro and in vivo, demonstrating that the G2032R solvent-front mutation is highly resistant to crizotinib, lorlatinib, and entrectinib but sensitive to DS-6051b.","method":"Cell-based growth inhibition assays (in vitro), xenograft mouse models (in vivo), profiling of resistance mutations in patient-derived cell models","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — cell-based and in vivo preclinical models with both WT and mutant ROS1; multiple orthogonal approaches in a single study","pmids":["31399568"],"is_preprint":false},{"year":2021,"finding":"ROS1 kinase domain mutations are the predominant resistance mechanism to crizotinib and lorlatinib in ROS1-positive NSCLC (identified in 38% post-crizotinib and 46% post-lorlatinib biopsies). G2032R is the most common (~1/3 of cases). A novel mutation, L2086F, was identified post-lorlatinib; structural modeling and Ba/F3 functional studies showed L2086F causes steric interference with lorlatinib, crizotinib, and entrectinib but accommodates cabozantinib, and cabozantinib produced disease control in a patient harboring L2086F.","method":"Clinical biopsy next-generation sequencing, structural modeling, Ba/F3 cell-based functional assays, clinical case report","journal":"Clinical cancer research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — clinical sequencing of 55 patients combined with structural modeling and Ba/F3 functional validation and clinical proof-of-concept; multiple orthogonal methods","pmids":["33685866"],"is_preprint":false},{"year":2021,"finding":"Entrectinib acts as a dual type I/II mode ROS1 inhibitor, making it liable to both gatekeeper/solvent-front (G2032R) and type II resistance mutations. Forward mutagenesis screens identified ROS1 F2004C as a recurrent entrectinib-resistant mutation and G2032R in entrectinib- and lorlatinib-resistant clones. ROS1 L2086F is broadly resistant to all type I inhibitors but remains sensitive to type II inhibitors (e.g., cabozantinib); ROS1 F2004C/I/V are resistant to type I and type II inhibitor cabozantinib but retain sensitivity to type I macrocyclic inhibitors.","method":"Unbiased forward mutagenesis screen in Ba/F3 CD74-ROS1 and EZR-ROS1 cells, cell-based inhibitor profiling, structural modeling","journal":"Molecular cancer therapeutics","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — unbiased mutagenesis screen with comprehensive cell-based validation across multiple inhibitors and structural modeling; multiple orthogonal methods in single study","pmids":["34907086"],"is_preprint":false}],"current_model":"ROS1 is an orphan receptor tyrosine kinase (ligand unknown in humans) that is transiently expressed during development in kidney, intestine, and lung; in cancer, chromosomal rearrangements fuse the constitutively active ROS1 kinase domain to diverse partner proteins, driving oncogenic signaling through the Ras/Raf/MEK/ERK, PI3K/Akt, and Vav3/cell-migration pathways; in normal vascular biology, reductive stress (glutathione accumulation due to GPX1 loss) activates ROS1 at Y2274 via s-glutathiolation and inhibition of the associated phosphatase SHP-2, promoting smooth muscle cell proliferation; in E-cadherin-deficient breast cells, ROS1 activity is required for normal cytokinesis, and its inhibition causes lethal mitotic failure; resistance to type I ROS1 inhibitors (crizotinib, entrectinib, lorlatinib) arises most commonly from acquired kinase domain mutations, especially the solvent-front G2032R, with additional mutations (L2086F, F2004C) conferring distinct resistance profiles that can be overcome by selective type II or macrocyclic inhibitors."},"narrative":{"mechanistic_narrative":"ROS1 is a transmembrane receptor tyrosine kinase that is transiently expressed during organ morphogenesis and is converted into a potent oncogenic driver by chromosomal rearrangement [PMID:1718742, PMID:22327623]. The gene was first identified as a tyrosine kinase-related oncogene activated by loss of its extracellular domain, with cell-type-specific expression in glioblastoma lines [PMID:3785223, PMID:2827175]. In normal development, c-ros is transiently expressed in kidney ureter epithelium, intestine, and lung, where it acts in mesenchymal–epithelial inductive interactions [PMID:1718742]. In cancer, gene fusions that retain the ROS1 kinase domain define a molecular subgroup of NSCLC and render the kinase constitutively active, driving proliferation through the Ras/Raf/MEK/ERK module, survival through PI3K, and migration through Vav3 [PMID:22327623, PMID:23719267, PMID:28465216]. ROS1 kinase activity is also engaged by reductive stress: GPX1 deficiency causes glutathione accumulation and s-glutathiolation of the ROS1-associated phosphatase SHP-2, relieving its inhibition and permitting ROS1 autophosphorylation at Y2274 to drive vascular smooth muscle cell proliferation [PMID:25401476]. ROS1 inhibition is synthetically lethal in E-cadherin (CDH1)-deficient breast cancer cells, where it is required for normal cytokinesis and proper p120 catenin localization [PMID:29610289]. Clinically, crizotinib produces marked responses in ROS1-rearranged NSCLC, establishing ROS1 as a validated therapeutic target [PMID:25264305], but resistance arises predominantly through kinase domain mutations—most commonly the solvent-front G2032R, with L2086F and F2004C conferring distinct, inhibitor-class-dependent resistance profiles addressable by selective, type II, or macrocyclic inhibitors [PMID:30093503, PMID:31399568, PMID:33685866, PMID:34907086].","teleology":[{"year":1986,"claim":"Establishing that ROS1 is a tyrosine kinase whose oncogenic form arises from loss of its extracellular domain answered whether MCF3 was a kinase oncogene and how it became activated.","evidence":"DNA-mediated gene transfer, tumorigenicity assay, and cDNA structural analysis","pmids":["3785223"],"confidence":"Medium","gaps":["No ligand or physiological substrate identified","Activation mechanism inferred from structure, not biochemically reconstituted"]},{"year":1987,"claim":"Mapping ROS1 expression and locus alterations in cancer cell lines established cell-type-specific expression and susceptibility to activating mutation, hinting at a role in malignancy.","evidence":"Northern/Southern blot survey of 45 cell lines, chromosomal mapping to 6q","pmids":["2827175","3329713"],"confidence":"Medium","gaps":["Functional consequence of the glioblastoma-line mutation not validated","No mechanistic link from 6q rearrangement to ROS1 activation"]},{"year":1991,"claim":"Demonstrating transient, tissue-restricted c-ros expression during organogenesis defined a normal developmental function as a receptor tyrosine kinase in inductive epithelial–mesenchymal interactions.","evidence":"RNase protection assay and in situ hybridization in mouse development","pmids":["1718742"],"confidence":"Medium","gaps":["Ligand remains unknown","Downstream developmental signaling not defined"]},{"year":2012,"claim":"Identifying recurrent ROS1 fusions in lung adenocarcinoma defined a distinct oncogenic NSCLC subgroup and shifted ROS1 from orphan oncogene to actionable driver.","evidence":"RT-PCR and FISH screening across 1,529 lung cancers","pmids":["22327623"],"confidence":"High","gaps":["Mechanism of constitutive activation for non-dimerizing partners not resolved","Partner-specific signaling differences not addressed"]},{"year":2013,"claim":"Linking ROS1 fusions to defined downstream cascades explained how the constitutively active kinase drives proliferation, survival, and migration.","evidence":"Synthesis of preclinical cell-based and in vivo signaling studies","pmids":["23719267"],"confidence":"Medium","gaps":["Relative contribution of each pathway to transformation not quantified","Direct substrates not enumerated"]},{"year":2014,"claim":"A phase I expansion cohort showing 72% response to crizotinib clinically validated ROS1 kinase activity as the oncogenic driver and therapeutic target in ROS1-rearranged NSCLC.","evidence":"Phase I clinical trial (n=50) with NGS/RT-PCR fusion typing","pmids":["25264305"],"confidence":"High","gaps":["Did not define resistance mechanisms","No correlation found between partner type and response, leaving partner biology open"]},{"year":2014,"claim":"Defining the GPX1–glutathione–SHP-2–ROS1 axis revealed a redox-regulated, non-oncogenic ROS1 activation mechanism driving pathological vascular remodeling.","evidence":"Gpx1 knockout mice, glutathiolation biochemistry, crizotinib inhibition, human cohort GWAS meta-analysis","pmids":["25401476"],"confidence":"High","gaps":["How ROS1 senses or couples to reductive stress upstream of SHP-2 not fully resolved","Endogenous ligand still unidentified"]},{"year":2015,"claim":"Structural comparison of ROS1 and ALK kinase domains explained inhibitor selectivity and showed that ROS1-selective inhibitors retain activity against the G2032R solvent-front mutant that escapes crizotinib.","evidence":"Molecular dynamics simulation and Ba/F3/patient-derived cell resistance profiling across seven compounds","pmids":["26372962"],"confidence":"High","gaps":["Predictions for some mutants based on modeling rather than crystal structures","Clinical activity of selective agents not yet established at this stage"]},{"year":2018,"claim":"Discovering synthetic lethality between ROS1 inhibition and CDH1 loss revealed a non-canonical ROS1 requirement in cytokinesis and a therapeutic vulnerability in E-cadherin-deficient breast cancer.","evidence":"CRISPR CDH1 engineering, genetic screens, pharmacological inhibition, mitotic imaging, and in vivo tumor models","pmids":["29610289"],"confidence":"High","gaps":["Direct ROS1 substrate controlling cytokinesis not identified","Mechanistic basis of CDH1-dependence not fully defined"]},{"year":2018,"claim":"Repotrectinib provided in vitro, in vivo, and clinical proof that macrocyclic TKIs overcome solvent-front (G2032R, D2033N) resistance, mapping resistance to the kinase active site.","evidence":"Kinase assays, mouse models, and phase I/II first-in-human trial","pmids":["30093503"],"confidence":"High","gaps":["Durability and resistance to repotrectinib not yet defined","Coverage of non-solvent-front mutations not fully tested"]},{"year":2021,"claim":"Systematic clinical sequencing and functional screens established kinase domain mutations as the dominant resistance mechanism and resolved inhibitor-class-specific profiles for G2032R, L2086F, and F2004C.","evidence":"Clinical biopsy NGS, Ba/F3 functional assays, structural modeling, forward mutagenesis screens, and DS-6051b/cabozantinib profiling","pmids":["33685866","34907086","31399568"],"confidence":"High","gaps":["No single inhibitor covers all resistance mutations","Compound/sequential resistance evolution not fully mapped"]},{"year":null,"claim":"The endogenous human ROS1 ligand and the mechanism of constitutive activation for non-dimerizing fusion partners remain undefined.","evidence":"No ligand-identification or activation-mechanism study for non-dimerizing fusions present in the corpus","pmids":[],"confidence":"Low","gaps":["Human ROS1 ligand unknown","Activation mechanism of CD74-ROS1 and other non-dimerizing fusions unresolved","Partner-dependent localization-to-substrate link not experimentally demonstrated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,5,7,10]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,5,10]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5,10]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,6,14]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[12]}],"complexes":[],"partners":["SHP-2","CD74","EZR","GPX1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P08922","full_name":"Proto-oncogene tyrosine-protein kinase ROS","aliases":["Proto-oncogene c-Ros","Proto-oncogene c-Ros-1","Receptor tyrosine kinase c-ros oncogene 1","c-Ros receptor tyrosine kinase"],"length_aa":2347,"mass_kda":263.9,"function":"Receptor tyrosine kinase (RTK) that plays a role in epithelial cell differentiation and regionalization of the proximal epididymal epithelium. NELL2 is an endogenous ligand for ROS1. Upon endogenous stimulation by NELL2, ROS1 activates the intracellular signaling pathway and triggers epididymal epithelial differentiation and subsequent sperm maturation (By similarity). May activate several downstream signaling pathways related to cell differentiation, proliferation, growth and survival including the PI3 kinase-mTOR signaling pathway. Mediates the phosphorylation of PTPN11, an activator of this pathway. May also phosphorylate and activate the transcription factor STAT3 to control anchorage-independent cell growth. Mediates the phosphorylation and the activation of VAV3, a guanine nucleotide exchange factor regulating cell morphology. May activate other downstream signaling proteins including AKT1, MAPK1, MAPK3, IRS1 and PLCG2","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/P08922/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ROS1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ROS1","total_profiled":1310},"omim":[{"mim_id":"621464","title":"LIMB- AND CNS-EXPRESSED GENE 1-LIKE; LIX1L","url":"https://www.omim.org/entry/621464"},{"mim_id":"611677","title":"OLFACTORY RECEPTOR, FAMILY 13, SUBFAMILY G, MEMBER 1; OR13G1","url":"https://www.omim.org/entry/611677"},{"mim_id":"609627","title":"TASTE RECEPTOR, TYPE 2, MEMBER 50; TAS2R50","url":"https://www.omim.org/entry/609627"},{"mim_id":"608092","title":"PALLADIN, CYTOSKELETAL-ASSOCIATED PROTEIN; PALLD","url":"https://www.omim.org/entry/608092"},{"mim_id":"606845","title":"GOLGI-ASSOCIATED PDZ AND COILED-COIL DOMAINS-CONTAINING PROTEIN; GOPC","url":"https://www.omim.org/entry/606845"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"epididymis","ntpm":55.3},{"tissue":"lung","ntpm":29.9}],"url":"https://www.proteinatlas.org/search/ROS1"},"hgnc":{"alias_symbol":["MCF3","ROS","c-ros-1"],"prev_symbol":[]},"alphafold":{"accession":"P08922","domains":[{"cath_id":"2.60.40.10","chopping":"107-188","consensus_level":"high","plddt":77.4827,"start":107,"end":188},{"cath_id":"2.60.40.10","chopping":"195-287","consensus_level":"medium","plddt":77.933,"start":195,"end":287},{"cath_id":"2.120.10.30","chopping":"292-549","consensus_level":"high","plddt":79.2828,"start":292,"end":549},{"cath_id":"2.120.10.30","chopping":"673-876_886-934","consensus_level":"medium","plddt":78.6859,"start":673,"end":934},{"cath_id":"2.60.40.10","chopping":"954-1036","consensus_level":"high","plddt":74.8117,"start":954,"end":1036},{"cath_id":"2.60.40.10","chopping":"1065-1097_1104-1147","consensus_level":"high","plddt":75.4908,"start":1065,"end":1147},{"cath_id":"2.120.10.30","chopping":"1205-1318","consensus_level":"medium","plddt":77.2336,"start":1205,"end":1318},{"cath_id":"2.60.40.10","chopping":"1460-1553","consensus_level":"medium","plddt":75.0774,"start":1460,"end":1553},{"cath_id":"2.60.40.10","chopping":"1664-1748","consensus_level":"medium","plddt":81.3751,"start":1664,"end":1748},{"cath_id":"2.60.40.10","chopping":"1761-1793_1803-1855","consensus_level":"high","plddt":76.9828,"start":1761,"end":1855},{"cath_id":"3.30.200.20","chopping":"1928-2029","consensus_level":"medium","plddt":80.382,"start":1928,"end":2029},{"cath_id":"1.10.510.10","chopping":"2034-2227","consensus_level":"medium","plddt":83.3251,"start":2034,"end":2227}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P08922","model_url":"https://alphafold.ebi.ac.uk/files/AF-P08922-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P08922-F1-predicted_aligned_error_v6.png","plddt_mean":72.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ROS1","jax_strain_url":"https://www.jax.org/strain/search?query=ROS1"},"sequence":{"accession":"P08922","fasta_url":"https://rest.uniprot.org/uniprotkb/P08922.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P08922/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P08922"}},"corpus_meta":[{"pmid":"24987008","id":"PMC_24987008","title":"Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release.","date":"2014","source":"Physiological reviews","url":"https://pubmed.ncbi.nlm.nih.gov/24987008","citation_count":4021,"is_preprint":false},{"pmid":"32231263","id":"PMC_32231263","title":"Reactive oxygen species (ROS) as pleiotropic physiological signalling agents.","date":"2020","source":"Nature reviews. 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The activated MCF3 form lacks gross rearrangements beyond loss of the extracellular domain.\",\n      \"method\": \"DNA-mediated gene transfer, tumorigenicity assay, structural analysis of cDNA\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — original characterization paper with DNA transfer, tumorigenicity assay, and structural analysis; single lab but multiple complementary methods\",\n      \"pmids\": [\"3785223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1987,\n      \"finding\": \"ROS1 is expressed at high levels specifically in glioblastoma-derived cell lines (but not in other cell lines) without gene amplification, and a potentially activating mutation at the ROS1 locus was detected in one glioblastoma line, indicating cell-type-specific expression and susceptibility to activating mutation.\",\n      \"method\": \"Northern blot survey of 45 cell lines, Southern blot copy-number analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic survey across 45 cell lines with two orthogonal methods (expression and copy number); single lab\",\n      \"pmids\": [\"2827175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1987,\n      \"finding\": \"The human ROS1 gene (formerly MCF3) maps to the distal half of chromosome 6q, a region frequently rearranged in malignant cells, suggesting involvement in diverse tumor types.\",\n      \"method\": \"Chromosomal mapping (somatic cell hybrid panel)\",\n      \"journal\": \"Oncogene research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single chromosomal mapping experiment; no functional validation\",\n      \"pmids\": [\"3329713\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"During mouse development, c-ros1 is transiently expressed in the kidney, intestine, and lung coinciding with major morphogenetic events; in the kidney, expression is confined to ureter epithelial cells involved in inductive interactions with metanephric mesenchyme, implicating ROS1 as a receptor tyrosine kinase in mesenchymal–epithelial inductive interactions.\",\n      \"method\": \"RNase protection assay, in situ hybridization\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal in vivo localization methods (RNase protection + in situ hybridization) with cell-type resolution; single lab\",\n      \"pmids\": [\"1718742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ROS1 gene fusions (with multiple partner genes) were identified in lung adenocarcinoma by integrated molecular screening; the resulting fusion proteins retain the ROS1 kinase domain and act as oncogenic drivers, defining a molecular subgroup of NSCLC.\",\n      \"method\": \"RT-PCR, fluorescence in situ hybridization (FISH), integrated histopathology-based screening in 1,529 lung cancers\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — large-scale systematic screen (n=1529) with orthogonal methods (RT-PCR + FISH) across multiple labs/institutions; independently replicated\",\n      \"pmids\": [\"22327623\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ROS1 chromosomal rearrangements create fusion proteins in which the ROS1 kinase domain becomes constitutively active and drives cellular proliferation; downstream signaling from ROS1 fusion proteins activates the Ras/Raf/MEK/ERK1/2 proliferation module, the PI3K cell survival pathway, and the Vav3 cell migration pathway.\",\n      \"method\": \"Review/synthesis of preclinical cell-based assays and in vivo models reported across multiple studies\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — synthesis of multiple independent cell-based experiments showing pathway activation; no single reconstitution experiment cited within the abstract\",\n      \"pmids\": [\"23719267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ROS1 inhibition with crizotinib showed marked antitumor activity in ROS1-rearranged NSCLC patients (72% objective response rate), establishing ROS1 kinase activity as an oncogenic driver and therapeutic target in this cancer subgroup. Seven distinct ROS1 fusion partners were identified; no correlation was observed between fusion partner type and clinical response to crizotinib.\",\n      \"method\": \"Phase I expansion cohort clinical trial (n=50), next-generation sequencing and RT-PCR for fusion partner identification, pharmacokinetics assessment\",\n      \"journal\": \"The New England journal of medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — prospective clinical trial with multiple orthogonal molecular analyses; replicated across subsequent independent cohorts\",\n      \"pmids\": [\"25264305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ROS1 kinase is activated by reductive stress downstream of GPX1 deficiency: loss of GPX1 leads to glutathione accumulation (reductive stress), which causes s-glutathiolation of the ROS1-associated phosphatase SHP-2, inhibiting SHP-2 and permitting ROS1 phosphorylation at activation site Y2274, thereby promoting vascular smooth muscle cell proliferation and pathological vascular remodeling. ROS1 inhibition with crizotinib abolished this proliferative effect without impairing endothelialization.\",\n      \"method\": \"Constitutive Gpx1 knockout mouse model, gene variant pair analysis in patient cohorts, genome-wide association meta-analysis, glutathiolation biochemistry, crizotinib pharmacological inhibition, in vivo vascular remodeling assay\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (genetic KO, biochemical glutathiolation assay, pharmacological inhibition, in vivo model, human cohort validation) in a single study; mechanistically rigorous\",\n      \"pmids\": [\"25401476\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Structural and molecular dynamics studies of the ROS1 kinase domain revealed distinct structural features distinguishing ROS1 from ALK that underlie differences in inhibitor selectivity. Cabozantinib and foretinib show striking selectivity for ROS1 over ALK. Cell-based resistance profiling demonstrated that ROS1-selective inhibitors retain efficacy against the CD74-ROS1(G2032R) solvent-front mutation whereas dual ROS1/ALK inhibitors (including crizotinib) are ineffective against this mutation.\",\n      \"method\": \"Molecular dynamics simulation, cell-based resistance profiling (Ba/F3 and patient-derived cell models), inhibitor selectivity assays across seven compounds\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — structural modeling validated by cell-based functional assays across multiple inhibitors and resistance mutants; single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"26372962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ROS1 fusion protein subcellular localization differs depending on the fusion partner: partners that retain transmembrane domains or dimerization domains influence whether ROS1 fusions localize to different subcellular compartments, suggesting that distinct fusions activate different substrates in vivo. Unlike ALK fusion proteins (activated by amino-terminal dimerization), several ROS1 fusion partners including CD74 apparently lack dimerization ability, leaving the mechanism of constitutive kinase activation for those fusions unknown.\",\n      \"method\": \"Literature synthesis, structural analysis of fusion protein domains\",\n      \"journal\": \"Future oncology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — inferred from domain analysis and literature review; no direct experimental validation of localization-dependent substrate differences in this paper\",\n      \"pmids\": [\"27256160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ROS1 protein-tyrosine kinase fusion proteins signal downstream through the Ras/Raf/MEK/ERK1/2 cell proliferation module, the PI3K cell survival pathway, and the Vav3 cell migration pathway. Crizotinib forms a complex within the front cleft between the small and large lobes of an active ROS1 protein-kinase domain and is classified as a type I inhibitor.\",\n      \"method\": \"Review of cell-based signaling studies; structural classification of inhibitor binding mode\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — synthesis of multiple independent cell-based experiments and structural data; consistent with prior mechanistic reports\",\n      \"pmids\": [\"28465216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Repotrectinib (TPX-0005), a macrocyclic TKI, is highly potent against ROS1 (including the solvent-front mutations G2032R and D2033N) and overcomes resistance to earlier-generation ROS1 inhibitors both in vitro and in vivo; confirmed responses were achieved in patients with ROS1 fusion-positive cancers that had relapsed on earlier-generation TKIs due to solvent-front substitution-mediated resistance.\",\n      \"method\": \"In vitro kinase assays, in vivo mouse models, phase I/II first-in-human clinical trial\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro assays plus in vivo models plus clinical proof-of-concept; multiple orthogonal methods confirming mechanistic basis of resistance overcome\",\n      \"pmids\": [\"30093503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ROS1 inhibition is synthetically lethal with E-cadherin (CDH1) deficiency in breast cancer cells. ROS1 inhibitors (foretinib, crizotinib) induced mitotic abnormalities, multinucleation, defective cytokinesis, and aberrant p120 catenin phosphorylation and localization specifically in E-cadherin-defective cells. In vivo, ROS1 inhibitors produced profound antitumor effects in multiple models of E-cadherin-defective breast cancer.\",\n      \"method\": \"CRISPR/Cas9-engineered CDH1 mutations, large-scale genetic perturbation screens in molecularly diverse breast tumor cell lines, pharmacological inhibition (foretinib, crizotinib), immunofluorescence for mitotic phenotypes, p120 catenin localization assays, in vivo mouse tumor models\",\n      \"journal\": \"Cancer discovery\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR genetic engineering plus large-scale screens plus pharmacological validation plus in vivo models; mechanistically linked to cytokinesis defect and p120 catenin mislocalization; replicated across multiple cell lines\",\n      \"pmids\": [\"29610289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DS-6051b, a selective ROS1/NTRK inhibitor, inhibits both wild-type ROS1 fusions and the crizotinib-resistant G2032R mutant ROS1 in vitro and in vivo, demonstrating that the G2032R solvent-front mutation is highly resistant to crizotinib, lorlatinib, and entrectinib but sensitive to DS-6051b.\",\n      \"method\": \"Cell-based growth inhibition assays (in vitro), xenograft mouse models (in vivo), profiling of resistance mutations in patient-derived cell models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — cell-based and in vivo preclinical models with both WT and mutant ROS1; multiple orthogonal approaches in a single study\",\n      \"pmids\": [\"31399568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ROS1 kinase domain mutations are the predominant resistance mechanism to crizotinib and lorlatinib in ROS1-positive NSCLC (identified in 38% post-crizotinib and 46% post-lorlatinib biopsies). G2032R is the most common (~1/3 of cases). A novel mutation, L2086F, was identified post-lorlatinib; structural modeling and Ba/F3 functional studies showed L2086F causes steric interference with lorlatinib, crizotinib, and entrectinib but accommodates cabozantinib, and cabozantinib produced disease control in a patient harboring L2086F.\",\n      \"method\": \"Clinical biopsy next-generation sequencing, structural modeling, Ba/F3 cell-based functional assays, clinical case report\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — clinical sequencing of 55 patients combined with structural modeling and Ba/F3 functional validation and clinical proof-of-concept; multiple orthogonal methods\",\n      \"pmids\": [\"33685866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Entrectinib acts as a dual type I/II mode ROS1 inhibitor, making it liable to both gatekeeper/solvent-front (G2032R) and type II resistance mutations. Forward mutagenesis screens identified ROS1 F2004C as a recurrent entrectinib-resistant mutation and G2032R in entrectinib- and lorlatinib-resistant clones. ROS1 L2086F is broadly resistant to all type I inhibitors but remains sensitive to type II inhibitors (e.g., cabozantinib); ROS1 F2004C/I/V are resistant to type I and type II inhibitor cabozantinib but retain sensitivity to type I macrocyclic inhibitors.\",\n      \"method\": \"Unbiased forward mutagenesis screen in Ba/F3 CD74-ROS1 and EZR-ROS1 cells, cell-based inhibitor profiling, structural modeling\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — unbiased mutagenesis screen with comprehensive cell-based validation across multiple inhibitors and structural modeling; multiple orthogonal methods in single study\",\n      \"pmids\": [\"34907086\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ROS1 is an orphan receptor tyrosine kinase (ligand unknown in humans) that is transiently expressed during development in kidney, intestine, and lung; in cancer, chromosomal rearrangements fuse the constitutively active ROS1 kinase domain to diverse partner proteins, driving oncogenic signaling through the Ras/Raf/MEK/ERK, PI3K/Akt, and Vav3/cell-migration pathways; in normal vascular biology, reductive stress (glutathione accumulation due to GPX1 loss) activates ROS1 at Y2274 via s-glutathiolation and inhibition of the associated phosphatase SHP-2, promoting smooth muscle cell proliferation; in E-cadherin-deficient breast cells, ROS1 activity is required for normal cytokinesis, and its inhibition causes lethal mitotic failure; resistance to type I ROS1 inhibitors (crizotinib, entrectinib, lorlatinib) arises most commonly from acquired kinase domain mutations, especially the solvent-front G2032R, with additional mutations (L2086F, F2004C) conferring distinct resistance profiles that can be overcome by selective type II or macrocyclic inhibitors.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ROS1 is a transmembrane receptor tyrosine kinase that is transiently expressed during organ morphogenesis and is converted into a potent oncogenic driver by chromosomal rearrangement [#3, #4]. The gene was first identified as a tyrosine kinase-related oncogene activated by loss of its extracellular domain, with cell-type-specific expression in glioblastoma lines [#0, #1]. In normal development, c-ros is transiently expressed in kidney ureter epithelium, intestine, and lung, where it acts in mesenchymal\\u2013epithelial inductive interactions [#3]. In cancer, gene fusions that retain the ROS1 kinase domain define a molecular subgroup of NSCLC and render the kinase constitutively active, driving proliferation through the Ras/Raf/MEK/ERK module, survival through PI3K, and migration through Vav3 [#4, #5, #10]. ROS1 kinase activity is also engaged by reductive stress: GPX1 deficiency causes glutathione accumulation and s-glutathiolation of the ROS1-associated phosphatase SHP-2, relieving its inhibition and permitting ROS1 autophosphorylation at Y2274 to drive vascular smooth muscle cell proliferation [#7]. ROS1 inhibition is synthetically lethal in E-cadherin (CDH1)-deficient breast cancer cells, where it is required for normal cytokinesis and proper p120 catenin localization [#12]. Clinically, crizotinib produces marked responses in ROS1-rearranged NSCLC, establishing ROS1 as a validated therapeutic target [#6], but resistance arises predominantly through kinase domain mutations\\u2014most commonly the solvent-front G2032R, with L2086F and F2004C conferring distinct, inhibitor-class-dependent resistance profiles addressable by selective, type II, or macrocyclic inhibitors [#11, #13, #14, #15].\",\n  \"teleology\": [\n    {\n      \"year\": 1986,\n      \"claim\": \"Establishing that ROS1 is a tyrosine kinase whose oncogenic form arises from loss of its extracellular domain answered whether MCF3 was a kinase oncogene and how it became activated.\",\n      \"evidence\": \"DNA-mediated gene transfer, tumorigenicity assay, and cDNA structural analysis\",\n      \"pmids\": [\"3785223\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No ligand or physiological substrate identified\", \"Activation mechanism inferred from structure, not biochemically reconstituted\"]\n    },\n    {\n      \"year\": 1987,\n      \"claim\": \"Mapping ROS1 expression and locus alterations in cancer cell lines established cell-type-specific expression and susceptibility to activating mutation, hinting at a role in malignancy.\",\n      \"evidence\": \"Northern/Southern blot survey of 45 cell lines, chromosomal mapping to 6q\",\n      \"pmids\": [\"2827175\", \"3329713\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the glioblastoma-line mutation not validated\", \"No mechanistic link from 6q rearrangement to ROS1 activation\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Demonstrating transient, tissue-restricted c-ros expression during organogenesis defined a normal developmental function as a receptor tyrosine kinase in inductive epithelial\\u2013mesenchymal interactions.\",\n      \"evidence\": \"RNase protection assay and in situ hybridization in mouse development\",\n      \"pmids\": [\"1718742\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ligand remains unknown\", \"Downstream developmental signaling not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identifying recurrent ROS1 fusions in lung adenocarcinoma defined a distinct oncogenic NSCLC subgroup and shifted ROS1 from orphan oncogene to actionable driver.\",\n      \"evidence\": \"RT-PCR and FISH screening across 1,529 lung cancers\",\n      \"pmids\": [\"22327623\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of constitutive activation for non-dimerizing partners not resolved\", \"Partner-specific signaling differences not addressed\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Linking ROS1 fusions to defined downstream cascades explained how the constitutively active kinase drives proliferation, survival, and migration.\",\n      \"evidence\": \"Synthesis of preclinical cell-based and in vivo signaling studies\",\n      \"pmids\": [\"23719267\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of each pathway to transformation not quantified\", \"Direct substrates not enumerated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"A phase I expansion cohort showing 72% response to crizotinib clinically validated ROS1 kinase activity as the oncogenic driver and therapeutic target in ROS1-rearranged NSCLC.\",\n      \"evidence\": \"Phase I clinical trial (n=50) with NGS/RT-PCR fusion typing\",\n      \"pmids\": [\"25264305\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define resistance mechanisms\", \"No correlation found between partner type and response, leaving partner biology open\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defining the GPX1\\u2013glutathione\\u2013SHP-2\\u2013ROS1 axis revealed a redox-regulated, non-oncogenic ROS1 activation mechanism driving pathological vascular remodeling.\",\n      \"evidence\": \"Gpx1 knockout mice, glutathiolation biochemistry, crizotinib inhibition, human cohort GWAS meta-analysis\",\n      \"pmids\": [\"25401476\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ROS1 senses or couples to reductive stress upstream of SHP-2 not fully resolved\", \"Endogenous ligand still unidentified\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Structural comparison of ROS1 and ALK kinase domains explained inhibitor selectivity and showed that ROS1-selective inhibitors retain activity against the G2032R solvent-front mutant that escapes crizotinib.\",\n      \"evidence\": \"Molecular dynamics simulation and Ba/F3/patient-derived cell resistance profiling across seven compounds\",\n      \"pmids\": [\"26372962\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Predictions for some mutants based on modeling rather than crystal structures\", \"Clinical activity of selective agents not yet established at this stage\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Discovering synthetic lethality between ROS1 inhibition and CDH1 loss revealed a non-canonical ROS1 requirement in cytokinesis and a therapeutic vulnerability in E-cadherin-deficient breast cancer.\",\n      \"evidence\": \"CRISPR CDH1 engineering, genetic screens, pharmacological inhibition, mitotic imaging, and in vivo tumor models\",\n      \"pmids\": [\"29610289\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct ROS1 substrate controlling cytokinesis not identified\", \"Mechanistic basis of CDH1-dependence not fully defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Repotrectinib provided in vitro, in vivo, and clinical proof that macrocyclic TKIs overcome solvent-front (G2032R, D2033N) resistance, mapping resistance to the kinase active site.\",\n      \"evidence\": \"Kinase assays, mouse models, and phase I/II first-in-human trial\",\n      \"pmids\": [\"30093503\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Durability and resistance to repotrectinib not yet defined\", \"Coverage of non-solvent-front mutations not fully tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Systematic clinical sequencing and functional screens established kinase domain mutations as the dominant resistance mechanism and resolved inhibitor-class-specific profiles for G2032R, L2086F, and F2004C.\",\n      \"evidence\": \"Clinical biopsy NGS, Ba/F3 functional assays, structural modeling, forward mutagenesis screens, and DS-6051b/cabozantinib profiling\",\n      \"pmids\": [\"33685866\", \"34907086\", \"31399568\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No single inhibitor covers all resistance mutations\", \"Compound/sequential resistance evolution not fully mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The endogenous human ROS1 ligand and the mechanism of constitutive activation for non-dimerizing fusion partners remain undefined.\",\n      \"evidence\": \"No ligand-identification or activation-mechanism study for non-dimerizing fusions present in the corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Human ROS1 ligand unknown\", \"Activation mechanism of CD74-ROS1 and other non-dimerizing fusions unresolved\", \"Partner-dependent localization-to-substrate link not experimentally demonstrated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 5, 7, 10]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 5, 10]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5, 10]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 6, 14]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"SHP-2\", \"CD74\", \"EZR\", \"GPX1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}