Affinage

PIK3CA

Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform · UniProt P42336

Length
1068 aa
Mass
124.3 kDa
Annotated
2026-06-10
100 papers in source corpus 22 papers cited in narrative 22 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PIK3CA encodes p110α, the catalytic subunit of class IA PI3K, a lipid kinase whose activity drives AKT-TOR signaling and downstream control of proliferation, migration, and metabolism; cancer-derived mutations confer gain-of-function by constitutively activating this pathway and transforming cells (PMID:17376864). Structurally, oncogenic substitutions cluster at interfaces between p110 domains and between p110 and the regulatory subunit p85α, where they disrupt inhibitory inter-domain contacts and provoke conformational changes in the kinase domain that elevate enzymatic output (PMID:18418043); the same logic extends to compound cis double mutations, which further relieve p85α inhibition and enhance membrane lipid binding to give supra-additive kinase activity and tumor growth (PMID:31699932). Beyond the canonical p110α/p85α/AKT axis, helical-domain mutants engage a distinct nuclear program in which dissociated p85β (PIK3R2) translocates to the nucleus, recruits the deubiquitinase USP7 to stabilize EZH1/EZH2, and enhances H3K27 trimethylation, a vulnerability exploited by combined PI3Kα and EZH inhibition (PMID:35418124). p110α abundance and activity are tuned post-translationally by opposing E3 ligases: NEDD4L drives proteasomal degradation while also being required to sustain AKT signaling (PMID:27339899), and TRAF6 mediates non-proteolytic activating ubiquitination upon serum stimulation (PMID:29729098); transcriptionally, p53 represses the PIK3CA promoter in a serine-46 phosphorylation-dependent manner (PMID:27401370). Mutant PIK3CA reprograms cell behavior and metabolism—inducing centrosome amplification through an AKT-ROCK-CDK2/Cyclin E-nucleophosmin pathway (PMID:29170395), driving mammary epithelial dedifferentiation to a multipotent stem-like state (PMID:26266975), and creating dependencies on glucose metabolism and the TCA enzyme OGDH for NAD+/NADH homeostasis (PMID:28396387). As a disease gene, PIK3CA is an oncogenic driver across breast, urothelial, pancreatic, lung, and myeloma contexts, frequently cooperating with KRAS or HER2 and converging on PI3Kα inhibitors such as BYL719/alpelisib (PMID:26567140, PMID:26640141, PMID:27465249, PMID:24766330), and somatic or germline activating mutations underlie vascular malformations, cerebral cavernous malformations, and Cowden syndrome (PMID:26637981, PMID:33910229, PMID:23246288).

Mechanistic history

Synthesis pass · year-by-year structured walk · 21 steps
  1. 2007 High

    Established that diverse cancer-derived PIK3CA mutations are bona fide gain-of-function alleles rather than passengers, defining PIK3CA as an oncogene acting through lipid kinase activity and AKT-TOR signaling.

    Evidence In vitro lipid kinase assays, chicken embryo fibroblast transformation, and AKT/TOR signaling readouts across 15 mutants with structural mapping

    PMID:17376864

    Open questions at the time
    • Three mechanistic groups proposed from modeling rather than direct structural determination
    • Did not resolve how each mutation class alters the enzyme at atomic resolution
  2. 2007 Medium

    Confirmed in human epithelial cells that common mutants exceed wild-type in promoting transformed phenotypes, linking mutation status to oncogenic potency.

    Evidence Ectopic expression of WT, K545E, and H1047R in airway epithelial cells with soft-agar and migration assays

    PMID:17803655

    Open questions at the time
    • Overexpression rather than endogenous expression
    • No biochemical link to kinase output in these cells
  3. 2008 High

    Provided the structural basis for activation by showing oncogenic mutations cluster at p110-p110 and p110-p85 interfaces, disrupting inhibitory contacts and reshaping the kinase domain.

    Evidence X-ray crystallography of the p110α/p85α complex with mapping of cancer mutations

    PMID:18418043

    Open questions at the time
    • Static structure does not capture membrane-bound active conformation
    • Helical vs kinase domain mutant mechanisms not fully separated structurally
  4. 2012 Medium

    Demonstrated that germline PIK3CA variants activate the pathway in patient cells, extending oncogenic mechanisms to a heritable overgrowth syndrome.

    Evidence Phospho-Thr308-AKT and PIP3 measurements in Cowden syndrome patient-derived cells

    PMID:23246288

    Open questions at the time
    • Limited mechanistic detail beyond signaling readouts
    • Single study, small patient cohort
  5. 2014 Medium

    Distinguished p110α from other class I isoforms as the non-redundant driver of constitutive AKT activity in a tumor context, supporting isoform-selective therapy.

    Evidence Isoform-specific shRNA and inhibitors (BYL-719 vs TGX-221, CAL-101, CAY10505) in multiple myeloma samples

    PMID:24766330

    Open questions at the time
    • Single lab
    • Mechanism of isoform selectivity in MM not defined
  6. 2015 High

    Showed mutant PIK3CA reprograms cell identity by dedifferentiating committed mammary epithelial cells to a multipotent state, with cell-of-origin dictating tumor malignancy.

    Evidence In situ lineage tracing and limiting-dilution transplantation in a conditional H1047R knock-in mouse

    PMID:26266975

    Open questions at the time
    • Molecular effectors of dedifferentiation not identified
    • Generalizability beyond mammary lineage unknown
  7. 2015 High

    Established genetic cooperation with KRAS and HER2 and identified compensatory ERK signaling as an escape route, framing PI3K as rate-limiting in early oncogenesis.

    Evidence Compound GEM models (KRAS/PIK3CA; Her2/inducible H1047R) with pathway blotting and MEK/Her2 inhibitor experiments

    PMID:26567140 PMID:26640141

    Open questions at the time
    • Pancreatic, lung, and mammary contexts may differ in cooperating effectors
    • ERK reactivation mechanism after PI3K loss not fully mapped
  8. 2015 High

    Demonstrated PIK3CA can initiate pancreatic tumorigenesis and that PI3K activation co-engages ERK signaling, broadening the oncogenic tissue spectrum.

    Evidence Pancreas-specific PIK3CA transgenic mice with histopathology and PI3K/mTOR inhibitor treatment

    PMID:26436951

    Open questions at the time
    • Link between PI3K and ERK activation mechanistically indirect
    • Constitutively active construct rather than endogenous hotspot allele
  9. 2015 High

    Systematically resolved variant-specific oncogenicity, showing potency only imperfectly tracks mutation frequency and that some variants additionally activate MEK1/2.

    Evidence High-throughput barcoded clone library with growth, soft-agar, in vivo, and proteomic profiling

    PMID:26627007

    Open questions at the time
    • Mechanism of MEK co-activation by specific variants unresolved
    • Overexpression system may not reflect endogenous levels
  10. 2015 High

    Linked PIK3CA mutations to vascular malformations and showed shared PI3K-dependent pathogenesis with TEK mutations, rescuable by PI3Kα inhibition.

    Evidence PIK3CA and TEK mutant expression in HUVECs with AKT/angiogenic readouts and BYL719 rescue

    PMID:26637981

    Open questions at the time
    • Endothelial-specific effectors downstream of AKT not detailed
    • In vitro HUVEC model
  11. 2016 High

    Identified NEDD4L as the E3 ligase driving proteasomal turnover of p110α while paradoxically being required to sustain AKT signaling, revealing nuanced post-translational control.

    Evidence Co-IP, ubiquitination assays, proteasome inhibition, and NEDD4L gain/loss-of-function with AKT readout

    PMID:27339899

    Open questions at the time
    • Mechanism of the paradoxical AKT requirement unexplained
    • Ubiquitin chain linkage type not defined
  12. 2016 Medium

    Defined transcriptional control of PIK3CA by p53, where serine-46 phosphorylation enables promoter repression and its loss confers drug resistance via sustained PIK3CA expression.

    Evidence Promoter-luciferase reporters, ChIP, and S46A mutagenesis in cisplatin-sensitive vs resistant cells

    PMID:27401370

    Open questions at the time
    • Single lab
    • Direct p53 binding site validation limited to reporter and ChIP
  13. 2016 Medium

    Confirmed mutant PIK3CA as a targetable driver in urothelial carcinoma, with inhibitor sensitivity gated by co-occurring pathway mutations.

    Evidence Mutant-specific shRNA knockdown and GDC-0941 sensitivity panel with in vivo tumor growth

    PMID:27465249

    Open questions at the time
    • Single lab
    • Mechanism by which TSC1/PTEN/AKT1/RAS mutations reduce sensitivity not dissected
  14. 2017 High

    Uncovered a metabolic dependency: PIK3CA-mutant cells require OGDH to maintain NAD+/NADH homeostasis via the malate-aspartate shuttle, exposing a metabolic vulnerability.

    Evidence Genome-scale RNAi screen, metabolic flux, OGDH knockdown, and metabolite rescue

    PMID:28396387

    Open questions at the time
    • How PI3K activation establishes OGDH dependency not fully mechanistic
    • Generalizability across tumor types untested
  15. 2017 High

    Showed endogenous H1047R drives centrosome amplification and tolerance to genome doubling through a defined AKT-ROCK-CDK2/Cyclin E-nucleophosmin pathway, linking PI3K to genome instability.

    Evidence Conditional endogenous-locus knock-in mouse with centrosome counting and AKT/ROCK/CDK2 inhibitor dissection

    PMID:29170395

    Open questions at the time
    • Connection between PI3K and centrosome machinery indirect
    • Contribution to tumor evolution in vivo not quantified
  16. 2018 Medium

    Identified TRAF6 as an activating, non-proteolytic E3 ligase for p110α under serum stimulation, providing a positive post-translational regulatory arm opposing NEDD4L.

    Evidence Reciprocal Co-IP, ubiquitination assays, and TRAF6 overexpression with AKT and growth readouts

    PMID:29729098

    Open questions at the time
    • Single lab
    • Ubiquitin chain topology and binding partner consequences not fully defined
    • No loss-of-function validation in physiological setting
  17. 2018 Medium

    Revealed a non-oncogenic physiological role: class I PI3K activity is spatially polarized to the MTOC and mitotic spindle pole to organize asymmetric lymphocyte division and receptor/glucose-transporter partitioning.

    Evidence PIP3 immunostaining, live imaging, and PI3K inhibitor perturbation in dividing T and B lymphocytes

    PMID:29420173

    Open questions at the time
    • Isoform-specific contribution of p110α not isolated
    • Mechanism establishing spatial restriction unknown
  18. 2019 High

    Demonstrated that cis double mutations are functionally synergistic, deepening p85α release and membrane binding to amplify kinase output and predict enhanced inhibitor sensitivity.

    Evidence In vitro PI3K activity, proliferation/tumor models, p85α binding assays, and cancer genome analysis

    PMID:31699932

    Open questions at the time
    • Structural basis of combined effects not crystallographically resolved
    • Clinical predictiveness requires patient validation
  19. 2021 High

    Showed that cerebral cavernous malformation growth requires combined PIK3CA gain-of-function and CCM-complex loss-of-function in the same endothelial cells, converging on mTOR and rescuable by rapamycin.

    Evidence Mouse genetic models, human CCM somatic mutation analysis, mTOR pathway analysis, rapamycin treatment

    PMID:33910229

    Open questions at the time
    • Order and timing of the two mutational events in human lesions unclear
    • Relative contributions of KLF4 vs PI3K to mTOR not quantified
  20. 2022 High

    Defined a domain-specific noncanonical mechanism whereby helical-domain mutants release p85β to the nucleus to stabilize EZH1/2 via USP7 and boost H3K27me3, creating a mutation-class-specific therapeutic vulnerability.

    Evidence Co-IP, nuclear fractionation, NLS mutagenesis, USP7/EZH stability assays, H3K27me3 ChIP, and alpelisib+tazemetostat xenografts

    PMID:35418124

    Open questions at the time
    • Genome-wide targets of nuclear p85β/EZH program not catalogued
    • Why only helical mutants release p85β structurally unresolved
  21. 2023 Medium

    Identified an mTORC1-independent axis in which E545K suppresses SIRT4 via EP300 to reprogram glutamine metabolism and DNA repair, with PI3Kα inhibition acting as a radiosensitizer.

    Evidence PIK3CA mutant cervical cancer models with EP300 inhibition, SIRT4/GPT1 manipulation, glutamine metabolism and radiosensitivity assays, and xenografts

    PMID:36646410

    Open questions at the time
    • Single lab
    • How E545K signals to EP300 independently of mTORC1 not mechanistically resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the distinct mutation classes (C2, helical, kinase) selectively wire to canonical AKT-mTOR output versus noncanonical nuclear p85β/EZH and mTOR-independent metabolic programs remains incompletely unified.
  • No single framework reconciles domain-specific canonical and noncanonical mechanisms
  • Membrane-bound active-state structure of mutant complexes not resolved
  • Integration of opposing NEDD4L/TRAF6 regulation in vivo unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 4 GO:0008289 lipid binding 3
Localization
GO:0005886 plasma membrane 2 GO:0005634 nucleus 1 GO:0005815 microtubule organizing center 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-1430728 Metabolism 2 R-HSA-4839726 Chromatin organization 1
Partners
EZH2NEDD4LPIK3R1PIK3R2TP53TRAF6USP7
Complex memberships
class IA PI3K (p110α/p85α)

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2007 Fifteen rare cancer-derived PIK3CA mutants were examined and 14 showed gain-of-function: they induced rapamycin-sensitive oncogenic transformation of chicken embryo fibroblasts, constitutively activated Akt and TOR-mediated signaling, and showed enhanced lipid kinase activity in vitro. Three mechanistic groups were proposed based on structural mapping: C2 domain mutants increase positive surface charge potentially enhancing membrane recruitment; helical domain mutants affect protein-protein interaction surfaces; kinase domain mutants alter the activation loop hinge position. In vitro lipid kinase assay, oncogenic transformation assay (chicken embryo fibroblasts), Akt/TOR signaling assays, structural modeling with mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 17376864
2008 Crystal structure of the p110α/p85α complex revealed that the majority of oncogenic PIK3CA mutations occur at interfaces between p110 domains and between p110 and p85 domains. At these positions, mutations disrupt inter-domain interactions causing conformational changes in the kinase domain that increase enzymatic activity. The structure also showed that membrane interaction is mediated by the iSH2 domain of p85. X-ray crystallography of p110α/p85α complex with structural mapping of cancer mutations Cell cycle (Georgetown, Tex.) High 18418043
2019 Double PIK3CA mutations occurring in cis on the same allele (found in 12–15% of breast cancers) result in increased PI3K lipid kinase activity, enhanced downstream AKT signaling, increased cell proliferation, and tumor growth compared to single hotspot mutations. Biochemical mechanisms include increased disruption of p110α binding to the inhibitory subunit p85α (relieving catalytic inhibition) and increased p110α membrane lipid binding. Double mutations predict enhanced sensitivity to PI3Kα inhibitors. In vitro PI3K activity assay, cell proliferation assays, tumor growth models, biochemical p85α binding assays, cancer genome analysis Science (New York, N.Y.) High 31699932
2016 NEDD4L was identified as the E3 ubiquitin ligase that catalyzes PIK3CA polyubiquitination, leading to proteasome-dependent degradation of p110α. NEDD4L ubiquitinates both free and regulatory subunit-bound PIK3CA but does not ubiquitinate the regulatory subunit p85. Overexpression of NEDD4L accelerates PIK3CA turnover, while suppression of NEDD4L increases PIK3CA levels and paradoxically decreases AKT activation, indicating NEDD4L is required for maintenance of PI3K-AKT signaling. Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor treatment, overexpression and knockdown of NEDD4L, Western blotting for AKT phosphorylation The Journal of biological chemistry High 27339899
2018 TRAF6 interacts with PIK3CA (p110α) and promotes its non-proteolytic polyubiquitination under serum stimulation. TRAF6 ubiquitinates both individual and regulatory subunit-bound PIK3CA but does not ubiquitinate the regulatory subunit. TRAF6 overexpression greatly enhances PI3K activation, leading to increased AKT phosphorylation and cell growth, establishing TRAF6 as a novel activating E3 ligase for PIK3CA. Co-immunoprecipitation, ubiquitination assay, TRAF6 overexpression with AKT phosphorylation readout, cell growth assay FEBS letters Medium 29729098
2017 PIK3CA mutant cancer cells exhibit increased reliance on glucose metabolism and specifically require the TCA cycle enzyme OGDH (2-oxoglutarate dehydrogenase). OGDH suppression in PIK3CA-mutant cells increases 2-oxoglutarate levels, leading to aspartate depletion, deregulation of the malate-aspartate shuttle, impaired cytoplasmic NAD+ regeneration, and a specific proliferative block due to inability to maintain NAD+/NADH homeostasis. Genome-scale RNAi loss-of-function screening in cancer cell lines, metabolic flux studies, OGDH knockdown, exogenous metabolite supplementation, NAD+/NADH measurement Proceedings of the National Academy of Sciences of the United States of America High 28396387
2017 Expression of the Pik3ca H1047R hotspot mutation from its endogenous locus in mouse cells induces centrosome amplification through a pathway involving AKT, ROCK, and CDK2/Cyclin E-nucleophosmin. Mutant Pik3ca also increases cellular tolerance to spontaneous genome doubling in vitro and in mouse tissues. Conditional knock-in mouse model (endogenous locus), centrosome counting, pathway inhibitor experiments (AKT, ROCK, CDK2 inhibitors), genome ploidy analysis Nature communications High 29170395
2015 PIK3CA H1047R expression in lineage-committed basal (Lgr5+) and luminal (K8+) mammary epithelial cells induces cell dedifferentiation into a multipotent stem-like state, demonstrated by in situ genetic lineage tracing and limiting dilution transplantation assays. The cell of origin of PIK3CA H1047R tumors dictates their malignancy. In situ genetic lineage tracing, limiting dilution transplantation, conditional PIK3CA H1047R knock-in mouse model Nature High 26266975
2015 PIK3CA H1047R expression alone failed to promote lung tumor formation but dramatically enhanced tumorigenesis initiated by KRAS G12D in genetically engineered mouse models. Oncogenic cooperation was accompanied by PI3Kα-mediated regulation of c-MYC, GSK3β, p27KIP1, survivin, and RB pathway components, resulting in accelerated cell division, indicating that PI3'-lipid signaling remains rate-limiting for cell-cycle progression of early-stage KRAS-initiated lung cells. Genetically engineered mouse models (GEM), compound KRAS/PIK3CA knock-in, Western blotting for pathway components, cell cycle analysis Cancer research High 26567140
2015 PIK3CA hotspot mutations (E542K, E545K, H1047R) cause chronic activation of AKT and dysregulation of angiogenic factors, and produce abnormal endothelial cell morphology when expressed in HUVECs. The p110α-specific inhibitor BYL719 restores all abnormal phenotypes in both PIK3CA-mutant and TEK-mutant HUVECs, demonstrating that PIK3CA and TEK mutations operate via the same PI3K-dependent pathogenic pathway in venous malformations. Expression of PIK3CA mutants in HUVECs, AKT phosphorylation assays, angiogenic factor measurement, morphology assays, pharmacological rescue with BYL719 American journal of human genetics High 26637981
2022 p85β (PIK3R2) dissociates from p110α helical domain mutant protein and translocates into the nucleus through a nuclear localization sequence (NLS). Nuclear p85β recruits deubiquitinase USP7 to stabilize EZH1 and EZH2, enhancing H3K27 trimethylation. Knockout of p85β or p85β NLS mutant reduces growth of PIK3CA helical domain mutant tumors. Combination of alpelisib and EZH inhibitor tazemetostat induced regression of PIK3CA helical domain mutant xenografts but not WT or kinase domain mutant tumors. Co-immunoprecipitation, nuclear fractionation, p85β NLS mutagenesis, USP7 interaction assay, EZH1/2 stability assay, H3K27me3 ChIP, xenograft models, genetic knockout Nature communications High 35418124
2016 p53 represses PIK3CA promoter activity through direct binding to p53 binding sequences in the PIK3CA promoter, and this repression depends on p53 phosphorylation at serine 46. In cisplatin-sensitive cells, cisplatin-induced p53 activation dynamically alters p53 occupancy at the PIK3CA promoter and attenuates PI3K/AKT signaling. In resistant cells, loss of p53 serine 46 phosphorylation abolishes PIK3CA promoter repression, resulting in sustained PIK3CA expression and cell survival. Promoter-luciferase reporter assay, chromatin immunoprecipitation (ChIP), p53 phosphorylation site mutagenesis (S46A), Western blotting, bioluminescent imaging in vivo Molecular oncology Medium 27401370
2015 Functional assessment of PIK3CA variants using high-throughput barcoded expression clones showed that PIK3CA variant oncogenic activity correlates imperfectly with mutation frequency in breast cancer. Mutations occurring above 5% frequency were significantly more oncogenic than wild-type in all assays, but lower frequency mutations varied from weak to strong oncogenicity. Proteomic profiling revealed variant-specific activation of PI3K signaling as well as MEK1/2 pathway activation depending on the specific PIK3CA mutation. High-throughput barcoded clone library, in vitro cell growth assay, soft agar transformation assay, in vivo tumor growth, proteomic profiling, therapeutic sensitivity assays Cancer research High 26627007
2015 PIK3CA mutations can initiate pancreatic tumorigenesis: expression of constitutively active PIK3CA in mouse pancreas increased acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasms (PanINs) as early as 10 days of age, with invasive pancreatic ductal adenocarcinoma by 20 days. These PIK3CA-mutant cancers showed phosphorylation of ERK1/2 in addition to PI3K pathway activation; ERK1/2 phosphorylation was diminished by dual PI3K/mTOR inhibition. Transgenic mouse models with pancreas-specific PIK3CA expression, histopathology, immunostaining, PI3K/mTOR inhibitor treatment Oncogenesis High 26436951
2021 Growth of cerebral cavernous malformations (CCMs) requires both somatic gain-of-function mutations in PIK3CA and loss-of-function mutations in CCM complex genes (KRIT1/CCM2/PDCD10) in the same endothelial cells. Mouse models showed that PIK3CA gain-of-function augments mTOR signaling in endothelial cells, and that both CCM loss-of-function and increased KLF4 (downstream of MEKK3) augment mTOR signaling. mTORC1 inhibitor rapamycin effectively blocked CCM formation in mouse models. Mouse genetic models, somatic mutation analysis of human CCMs, mTOR pathway analysis, rapamycin treatment in vivo Nature High 33910229
2015 Induction of PIK3CA H1047R in mouse mammary glands with constitutive activated Her2/Neu resulted in accelerated mammary tumorigenesis with enhanced metastatic potential. PIK3CA H1047R expression caused robust PI3K/AKT signaling activation but attenuated Her2/Her3 signaling. Tumors that escaped PI3K dependence after PIK3CA H1047R inactivation did so through compensatory ERK activation, which could be blocked by combined inhibition of Her2 and MEK. Compound transgenic mouse model (Her2 + inducible PIK3CA H1047R), deinduction of PIK3CA H1047R, Western blotting for pathway components, MEK and Her2 inhibitor treatment Oncogene High 26640141
2018 In activated T and B lymphocytes, class I PI3K (indexed by PIP3) activity is spatially restricted to the microtubule-organizing center and then to one pole of the mitotic spindle, creating asymmetry. Asymmetric PI3K activity co-localizes with asymmetric distribution of antigen receptor components and glucose transporters (whose trafficking is PI3K-dependent). Perturbation of class I PI3K activity disrupts asymmetry of upstream antigen receptors and downstream glucose transporter trafficking, establishing PI3K as a core organizer of lymphocyte polarity and asymmetric cell division. PIP3 immunostaining in dividing lymphocytes, live imaging, PI3K inhibitor perturbation, glucose transporter trafficking assay Cell reports Medium 29420173
2023 PIK3CA E545K mutation negatively regulates SIRT4 expression through the epigenetic regulator EP300, independently of the canonical mTORC1 pathway. PIK3CA-E545K-induced SIRT4 downregulation promoted cell proliferation, migration, radiation-induced DNA repair, and reduced apoptosis in cervical cancer cells. SIRT4 modulates glutamine metabolism and cellular apoptosis by negatively regulating glutamate pyruvate transaminase GPT1. PI3K inhibitor BYL719 (but not mTOR inhibitors) had synergistic radiosensitizing effects by inhibiting glutamine metabolism. PIK3CA mutant cell line models, EP300 inhibition, SIRT4 overexpression/knockdown, GPT1 activity assay, glutamine metabolism measurement, radiosensitivity assay, in vivo xenograft Cancer letters Medium 36646410
2007 Overexpression of wild-type PIK3CA and its two common mutants K545E and H1047R significantly enhanced anchorage-independent growth activity and migration activity of immortalized human airway epithelial cells (16HBE14o-), with the effects of K545E and H1047R mutants being more pronounced than wild-type. Ectopic expression in human airway epithelial cell line, anchorage-independent growth assay (soft agar), migration assay Pathology international Medium 17803655
2016 Specific knockdown of mutant PIK3CA in urothelial carcinoma (UC) cell lines inhibited PI3K pathway activation, cell proliferation, migration, anchorage-independent growth, and in vivo tumor growth, establishing mutant PIK3CA as a potent oncogenic driver in UC. Sensitivity to the class I PI3K inhibitor GDC-0941 was dependent on hotspot PIK3CA mutation status; cells with co-occurring TSC1, PTEN, AKT1, or RAS mutations were less sensitive. Retrovirus-mediated shRNA knockdown of mutant PIK3CA, proliferation, migration, anchorage-independent growth assays, in vivo tumor growth, GDC-0941 sensitivity panel BMC cancer Medium 27465249
2014 PIK3CA isoform-specific knockdown experiments in multiple myeloma cells showed that PIK3CA (p110α) is of paramount importance for constitutive AKT activity in MM cells. Unlike knockdown of PIK3CB, PIK3CD, or PIK3CG, only PIK3CA knockdown or pharmacological PIK3CA inhibition with BYL-719 was sufficient to induce cell death in a sizeable subgroup of MM samples. Isoform-specific shRNA knockdown (PIK3CA, PIK3CB, PIK3CD, PIK3CG), isoform-specific inhibitors (BYL-719, TGX-221, CAL-101, CAY10505), AKT phosphorylation assay, cell viability assay British journal of haematology Medium 24766330
2012 Germline PIK3CA mutations in Cowden syndrome patients result in significantly increased phospho-Thr308-AKT and increased cellular PIP3 levels compared to wild-type, directly demonstrating that these germline PIK3CA variants activate PI3K pathway signaling. Cell signaling assays (phospho-AKT, PIP3 measurement) in patient-derived cells with germline PIK3CA mutations American journal of human genetics Medium 23246288

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer research 779 15520168
2012 Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. The New England journal of medicine 691 23094721
2005 PIK3CA gene is frequently mutated in breast carcinomas and hepatocellular carcinomas. Oncogene 445 15608678
2006 Mutation of the PIK3CA oncogene in human cancers. British journal of cancer 407 16449998
2012 PI3K/AKT/mTOR inhibitors in patients with breast and gynecologic malignancies harboring PIK3CA mutations. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 396 22271473
2005 Frequent mutation of the PIK3CA gene in ovarian and breast cancers. Clinical cancer research : an official journal of the American Association for Cancer Research 373 15837735
2007 Rare cancer-specific mutations in PIK3CA show gain of function. Proceedings of the National Academy of Sciences of the United States of America 346 17376864
2020 Frequency and spectrum of PIK3CA somatic mutations in breast cancer. Breast cancer research : BCR 284 32404150
2005 Mutation of the PIK3CA gene in anaplastic thyroid cancer. Cancer research 274 16288007
2015 Somatic Activating PIK3CA Mutations Cause Venous Malformation. American journal of human genetics 268 26637981
2015 PIK3CA(H1047R) induces multipotency and multi-lineage mammary tumours. Nature 260 26266975
2019 Double PIK3CA mutations in cis increase oncogenicity and sensitivity to PI3Kα inhibitors. Science (New York, N.Y.) 238 31699932
2018 Cancer-Associated PIK3CA Mutations in Overgrowth Disorders. Trends in molecular medicine 219 30197175
2014 Assessing PIK3CA and PTEN in early-phase trials with PI3K/AKT/mTOR inhibitors. Cell reports 206 24440717
2013 Phosphatidylinositol 3-kinase (PI3K) inhibitors as cancer therapeutics. Journal of hematology & oncology 204 24261963
2008 PIK3CA mutation in colorectal cancer: relationship with genetic and epigenetic alterations. Neoplasia (New York, N.Y.) 204 18516290
2006 PIK3CA mutations in head and neck squamous cell carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research 184 16533766
2006 PIK3CA and PTEN mutations in uterine endometrioid carcinoma and complex atypical hyperplasia. Clinical cancer research : an official journal of the American Association for Cancer Research 176 17062663
2019 PIK3CA in cancer: The past 30 years. Seminars in cancer biology 171 30742905
2021 PIK3CA and CCM mutations fuel cavernomas through a cancer-like mechanism. Nature 157 33910229
2015 Identification of Variant-Specific Functions of PIK3CA by Rapid Phenotyping of Rare Mutations. Cancer research 145 26627007
2012 Germline PIK3CA and AKT1 mutations in Cowden and Cowden-like syndromes. American journal of human genetics 136 23246288
2006 PIK3CA gene mutations in pediatric and adult glioblastoma multiforme. Molecular cancer research : MCR 131 17050665
2014 Loss of ARID1A expression sensitizes cancer cells to PI3K- and AKT-inhibition. Oncotarget 126 24979463
2018 Characterization of PIK3CA and PIK3R1 somatic mutations in Chinese breast cancer patients. Nature communications 123 29636477
2022 Immunogenicity and therapeutic targeting of a public neoantigen derived from mutated PIK3CA. Nature medicine 119 35484264
2014 PIK3CA mutations in breast cancer: reconciling findings from preclinical and clinical data. Breast cancer research : BCR 116 25192370
2007 PIK3CA mutation and amplification in human lung cancer. Pathology international 114 17803655
2014 PIK3CA in Colorectal Cancer. Frontiers in oncology 106 24624362
2021 Somatic PIK3CA Mutations in Sporadic Cerebral Cavernous Malformations. The New England journal of medicine 95 34496175
2022 PIK3CA-mutations in breast cancer. Breast cancer research and treatment 92 36279023
2016 CLOVES syndrome: review of a PIK3CA-related overgrowth spectrum (PROS). Clinical genetics 91 27426476
2008 Frequent mutations and amplifications of the PIK3CA gene in pituitary tumors. Endocrine-related cancer 81 18852163
2019 Targeting the PI3K/Akt/mTOR pathway with the pan-Akt inhibitor GDC-0068 in PIK3CA-mutant breast cancer brain metastases. Neuro-oncology 79 31173106
2020 Activating AKT1 and PIK3CA Mutations in Metastatic Castration-Resistant Prostate Cancer. European urology 77 32451180
2019 Megalencephaly syndromes associated with mutations of core components of the PI3K-AKT-MTOR pathway: PIK3CA, PIK3R2, AKT3, and MTOR. American journal of medical genetics. Part C, Seminars in medical genetics 73 31441589
2006 Mutation analysis of PIK3CA and PIK3CB in esophageal cancer and Barrett's esophagus. International journal of cancer 70 16380997
2019 The Dual PI3K/mTOR Pathway Inhibitor GDC-0084 Achieves Antitumor Activity in PIK3CA-Mutant Breast Cancer Brain Metastases. Clinical cancer research : an official journal of the American Association for Cancer Research 69 30796030
2008 Insights into the oncogenic effects of PIK3CA mutations from the structure of p110alpha/p85alpha. Cell cycle (Georgetown, Tex.) 65 18418043
2020 PIK3CA Mutation in HPV-Associated OPSCC Patients Receiving Deintensified Chemoradiation. Journal of the National Cancer Institute 63 31747025
2013 Genetic deregulation of the PIK3CA oncogene in oral cancer. Cancer letters 63 23597702
2020 Managing toxicities of phosphatidylinositol-3-kinase (PI3K) inhibitors. Hematology. American Society of Hematology. Education Program 62 33275709
2015 PIK3CA mutations can initiate pancreatic tumorigenesis and are targetable with PI3K inhibitors. Oncogenesis 62 26436951
2017 Oncogenic PIK3CA induces centrosome amplification and tolerance to genome doubling. Nature communications 59 29170395
2014 Signaling intermediates (MAPK and PI3K) as therapeutic targets in NSCLC. Current pharmaceutical design 59 24138714
2012 Clinicopathologic and biological analysis of PIK3CA mutation in ovarian clear cell carcinoma. Human pathology 58 22705003
2016 Nephroblastomatosis or Wilms tumor in a fourth patient with a somatic PIK3CA mutation. American journal of medical genetics. Part A 56 27191687
2012 PI3K expression and PIK3CA mutations are related to colorectal cancer metastases. World journal of gastroenterology 56 22851869
2017 Dual PI3K/mTOR Inhibition in Colorectal Cancers with APC and PIK3CA Mutations. Molecular cancer research : MCR 53 28184015
2009 Frequent PIK3CA gene amplification and its clinical significance in colorectal cancer. The Journal of pathology 51 19697359
2008 The PIK3CA gene as a mutated target for cancer therapy. Current cancer drug targets 50 19075596
2015 Gene of the month: PIK3CA. Journal of clinical pathology 47 25688137
2016 Mutation distributions and clinical correlations of PIK3CA gene mutations in breast cancer. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 45 26921096
2014 KRAS, BRAF and PIK3CA status in squamous cell anal carcinoma (SCAC). PloS one 45 24642661
2019 PIK3CA mutations in vascular malformations. Current opinion in hematology 44 30855339
2017 PIK3CA mutant tumors depend on oxoglutarate dehydrogenase. Proceedings of the National Academy of Sciences of the United States of America 43 28396387
2016 NEDD4L Protein Catalyzes Ubiquitination of PIK3CA Protein and Regulates PI3K-AKT Signaling. The Journal of biological chemistry 41 27339899
2018 PI3K pathway in prostate cancer: All resistant roads lead to PI3K. Biochimica et biophysica acta. Reviews on cancer 38 30300679
2014 MYC-xing it up with PIK3CA mutation and resistance to PI3K inhibitors: summit of two giants in breast cancers. American journal of cancer research 38 25628917
2008 PIK3CA, HRAS and KRAS gene mutations in human penile cancer. The Journal of urology 38 18355852
2022 PIK3CA mutations-mediated downregulation of circLHFPL2 inhibits colorectal cancer progression via upregulating PTEN. Molecular cancer 37 35619132
2020 PIK3CA mutation enrichment and quantitation from blood and tissue. Scientific reports 35 33051521
2015 PIK3CA(H1047R)- and Her2-initiated mammary tumors escape PI3K dependency by compensatory activation of MEK-ERK signaling. Oncogene 35 26640141
2020 PIK3CA vascular overgrowth syndromes: an update. Current opinion in pediatrics 34 32692051
2020 PIK3CA gene aberrancy and role in targeted therapy of solid malignancies. Cancer gene therapy 33 31988478
2013 Mouse models of PIK3CA mutations: one mutation initiates heterogeneous mammary tumors. The FEBS journal 33 23384338
2008 PIK3CA mutation status in Japanese esophageal squamous cell carcinoma. The Journal of surgical research 33 18262558
2015 PIK3CA(H1047R) Accelerates and Enhances KRAS(G12D)-Driven Lung Tumorigenesis. Cancer research 32 26567140
2024 PI3K PROTAC overcomes the lapatinib resistance in PIK3CA-mutant HER2 positive breast cancer. Cancer letters 30 38986734
2022 Nuclear translocation of p85β promotes tumorigenesis of PIK3CA helical domain mutant cancer. Nature communications 30 35418124
2018 Asymmetric PI3K Activity in Lymphocytes Organized by a PI3K-Mediated Polarity Pathway. Cell reports 30 29420173
2018 CDKN2A loss and PIK3CA mutation in myoepithelial-like metaplastic breast cancer. The Journal of pathology 30 29708279
2019 Expression and significance of EBV, ARID1A and PIK3CA in gastric carcinoma. Molecular medicine reports 29 30747208
2012 Mutation and genomic amplification of the PIK3CA proto-oncogene in pituitary adenomas. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas 29 22782554
2024 Alpelisib for PIK3CA-mutated advanced gynecological cancers: First clues of clinical activity. Gynecologic oncology 28 38518529
2013 EGFR, KRAS, BRAF, and PIK3CA characterization in squamous cell anal cancer. Histology and histopathology 28 24122611
2024 Regulation of PI3K signaling in cancer metabolism and PI3K-targeting therapy. Translational breast cancer research : a journal focusing on translational research in breast cancer 27 39534586
2020 Aspirin has a better effect on PIK3CA mutant colorectal cancer cells by PI3K/Akt/Raptor pathway. Molecular medicine (Cambridge, Mass.) 27 32000660
2016 PIK3CA dependence and sensitivity to therapeutic targeting in urothelial carcinoma. BMC cancer 27 27465249
2009 FGFR3 and PIK3CA mutations in stucco keratosis and dermatosis papulosa nigra. The British journal of dermatology 26 19845664
2023 The PIK3CA-E545K-SIRT4 signaling axis reduces radiosensitivity by promoting glutamine metabolism in cervical cancer. Cancer letters 25 36646410
2018 TRAF6 interacts with and ubiquitinates PIK3CA to enhance PI3K activation. FEBS letters 23 29729098
2017 Analysis of PIK3CA mutations and PI3K pathway proteins in advanced gastric cancer. The Journal of surgical research 23 28550907
2017 [PIK3CA-related overgrowth syndrome (PROS)]. Nephrologie & therapeutique 22 28577738
2014 Molecular alterations of PIK3CA in uterine carcinosarcoma, clear cell, and serous tumors. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society 22 25078343
2013 Carcinogenesis of PIK3CA. Hereditary cancer in clinical practice 22 23768168
2023 Endothelial hyperactivation of mutant MAP3K3 induces cerebral cavernous malformation enhanced by PIK3CA GOF mutation. Angiogenesis 21 36719480
2021 Use of Liquid Biopsy to Detect PIK3CA Mutation in Metastatic Breast Cancer. Journal of Nippon Medical School = Nippon Ika Daigaku zasshi 21 33692304
2021 EZH2 inhibition confers PIK3CA-driven lung tumors enhanced sensitivity to PI3K inhibition. Cancer letters 21 34655667
2023 PIK3CA is recurrently mutated in canine mammary tumors, similarly to in human mammary neoplasia. Scientific reports 20 36635367
2023 Multiple PIK3CA mutation clonality correlates with outcomes in taselisib + fulvestrant-treated ER+/HER2-, PIK3CA-mutated breast cancers. Genome medicine 20 37101291
2016 p53 Loses grip on PIK3CA expression leading to enhanced cell survival during platinum resistance. Molecular oncology 20 27401370
2014 PIK3CA and PIK3CB expression and relationship with multidrug resistance in colorectal carcinoma. International journal of clinical and experimental pathology 20 25550888
2016 Triggering PIK3CA Mutations in PI3K/Akt/mTOR Axis: Exploration of Newer Inhibitors and Rational Preventive Strategies. Current pharmaceutical design 19 27296758
2014 PI3K-dependent multiple myeloma cell survival is mediated by the PIK3CA isoform. British journal of haematology 19 24766330
2014 Relationship of PIK3CA mutation and pathway activity with antiproliferative response to aromatase inhibition. Breast cancer research : BCR 19 24981670
2012 Initiating breast cancer by PIK3CA mutation. Breast cancer research : BCR 19 22315990
2024 Understanding PI3K/Akt/mTOR signaling in squamous cell carcinoma: mutated PIK3CA as an example. Molecular biomedicine 18 38616230
2024 PIK3CA mutations in endocrine-resistant breast cancer. Scientific reports 18 38822093
2024 PIK3CA inhibition in models of proliferative glomerulonephritis and lupus nephritis. The Journal of clinical investigation 17 38842935

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