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| Profile Name | PIK3CA act mut |
| Gene Variant Detail | |
| Relevant Treatment Approaches | Akt Inhibitor (Pan) Akt1 Inhibitor Akt2 Inhibitor mTOR Inhibitor mTORC1 Inhibitor mTORC2 Inhibitor PI3K Inhibitor (Pan) PIK3CA inhibitor |
| Molecular Profile | Indication/Tumor Type | Response Type | Relevant Treatment Approaches | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|---|
| PIK3CA act mut | lung non-small cell carcinoma | sensitive | PI3K Inhibitor (Pan) | Pictilisib | Preclinical - Cell line xenograft | Actionable | In preclinical studies, the PI3K inhibitor GDC-0941 demonstrated efficacy against NSCLC tumor cell lines in culture and in xenograft models harboring alterations in the PI3K pathway (PMID: 23136191). | 23136191 |
| PIK3CA act mut | Advanced Solid Tumor | conflicting | PIK3CA inhibitor | Taselisib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, Taselisib (GDC-0032) effectively suppressed growth of multiple tumor types in cell line xenograft models, with greater selectivity for PIK3CA activating mutants (PMID: 23662903). | 23662903 |
| PIK3CA act mut | breast cancer | sensitive | PIK3CA inhibitor | Copanlisib | Preclinical | Actionable | In a preclinical study, breast cancer cell lines with a PIK3CA activating mutation and/or ERBB2 (HER2) over expression demonstrated increased sensitivity to inhibition of proliferation by Aliqopa (copanlisib) in culture, compared to ERBB2 (HER2)-negative and wild-type PIK3CA cell lines (PMID: 24170767). | 24170767 |
| PIK3CA act mut | Advanced Solid Tumor | sensitive | Akt1 Inhibitor Akt2 Inhibitor | BAY1125976 | Preclinical | Actionable | In a preclinical study, BAY1125976 demonstrated anti-tumor efficacy in multiple xenograft tumor models of different cancers with PIK3CA mutations or PTEN deletions and displayed synergy with other anti-cancer therapies (Cancer Res 2013;73(8 Suppl):Abstract nr 2050). | detail... |
| PIK3CA act mut | Advanced Solid Tumor | sensitive | mTORC1 Inhibitor | Everolimus | Preclinical - Cell line xenograft | Actionable | In a preclinical study, Afinitor (everolimus) demonstrated efficacy in multiple cancer cell lines in culture and xenograft models with PIK3CA activating mutations (PMID: 20664172). | 20664172 |
| PIK3CA act mut | Advanced Solid Tumor | sensitive | mTOR Inhibitor | Metformin | Preclinical | Actionable | In a preclinical study, Glucophage (metformin) demonstrated efficacy in treating dietary restriction-resistant human xenograft tumors harboring a PIK3CA-activating mutation (PMID: 23986086). | 23986086 |
| PIK3CA act mut | Advanced Solid Tumor | sensitive | Akt Inhibitor (Pan) | Ipatasertib + Paclitaxel | Phase I | Actionable | In a Phase Ib trial, the combination of Ipatasertib (GDC-0068) and Taxol (paclitaxel) resulted in an objective response rate (ORR) of 8.0% (2/25, partial responses) in patients with advanced solid tumors (n=25), and ORR was proportionally higher in patients harboring activating PIK3CA mutations (2/6) compared to patients without PIK3CA activating mutations (0/19) (PMID: 32205017; NCT01362374). | 32205017 |
| PIK3CA act mut | Advanced Solid Tumor | sensitive | Akt Inhibitor (Pan) | Afuresertib | Preclinical | Actionable | In a preclinical study, various tumor cell lines harboring PI3KCA activating mutations demonstrated increased sensitivity to Afuresertib (GSK2110183) in cultured cells (PMID: 24978597). | 24978597 |
| PIK3CA act mut | breast cancer | sensitive | Akt Inhibitor (Pan) | MK2206 | Preclinical | Actionable | In a preclinical study, breast cancer cell lines harboring activating mutations in PIK3CA had increased sensitivity to MK2206 in cell culture (PMID: 22932669). | 22932669 |
| PIK3CA act mut | head and neck squamous cell carcinoma | sensitive | mTOR Inhibitor PI3K Inhibitor (Pan) | Gedatolisib | Preclinical | Actionable | In a preclinical study, PF-05212384 decreased viability of head and neck squamous carcinoma cells harboring a PIK3CA activating mutation in cell culture (PMID: 24823695). | 24823695 |
| PIK3CA act mut | ovarian clear cell adenocarcinoma | sensitive | mTOR Inhibitor PI3K Inhibitor (Pan) | Dactolisib | Preclinical | Actionable | In a preclinical study, BEZ235 demonstrated efficacy in mouse xenograft models of ovarian clear cell adenocarcinoma with PIK3CA mutations (PMID: 24927217). | 24927217 |
| PIK3CA act mut | breast cancer | predicted - sensitive | Akt Inhibitor (Pan) mTORC1 Inhibitor | MK2206 + Ridaforolimus | Phase I | Actionable | In a Phase I clinical trial, Ridaforolimus in combination with MK-2206 demonstrated clinical activity in breast cancer patients expressing a PI3K pathway dependent gene expression signature, with complete response in 14.3% (2/14), partial response in 12.5% (2/16), and 2 patients achieving stable disease (PMID: 26187616). | 26187616 |
| PIK3CA act mut | Advanced Solid Tumor | sensitive | mTOR Inhibitor PI3K Inhibitor (Pan) | GSK1059615 | Preclinical | Actionable | In a preclinical study, solid tumor cell lines harboring PIK3CA activating mutations demonstrated increased sensitivity to GSK1059615 in culture (Clin Cancer Res October 1, 2008 14; B37). | detail... |
| PIK3CA act mut | lung small cell carcinoma | predicted - sensitive | PI3K Inhibitor (Pan) | Navitoclax + Pictilisib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, the combination of Navitoclax (ABT-263) and GDC-0941 resulted in increased tumor growth delay and apoptosis in a small cell lung cancer cell line xenograft model harboring a PIK3CA activating mutation compared to either drug alone (PMID: 27197306). | 27197306 |
| PIK3CA act mut | estrogen-receptor positive breast cancer | predicted - sensitive | Akt Inhibitor (Pan) | Capivasertib + Tamoxifen | Preclinical - Cell culture | Actionable | In a preclinical study, the combination of AZD5363 and 4-hydroxytamoxifen (4-OHT) worked synergistically or additively to inhibit growth of several estrogen receptor-positive breast cancer cell lines in culture, including cell lines with PIK3CA activating mutations, and overcame tamoxifen resistance in a resistant cell line (PMID: 26116361). | 26116361 |
| PIK3CA act mut | breast cancer | no benefit | mTOR Inhibitor PI3K Inhibitor (Pan) | Dactolisib + Venetoclax | Preclinical - Cell culture | Actionable | In a preclinical study, inhibition of Pi3k signaling by BEZ235 did not sensitize breast cancer cell lines harboring PIK3CA activating mutations to Venclexta (venetoclax) in culture (PMID: 27974663). | 27974663 |
| PIK3CA act mut | breast cancer | predicted - sensitive | mTOR Inhibitor PI3K Inhibitor (Pan) | Dactolisib + WEHI-539 | Preclinical - Cell culture | Actionable | In a preclinical study, inhibition of Pi3k signaling by BEZ235 sensitized breast cancer cell lines harboring PIK3CA activating mutations to WEHI-539 in culture (PMID: 27974663). | 27974663 |
| PIK3CA act mut | breast cancer | no benefit | PI3K Inhibitor (Pan) | Buparlisib + WEHI-539 | Preclinical - Cell culture | Actionable | In a preclinical study, Buparlisib (BKM120) did not sensitize breast cancer cell lines harboring PIK3CA activating mutations to WEHI-539 in culture (PMID: 27974663). | 27974663 |
| PIK3CA act mut | breast cancer | no benefit | PIK3CA inhibitor | Alpelisib + WEHI-539 | Preclinical - Cell culture | Actionable | In a preclinical study, Alpelisib (BYL719) did not sensitize breast cancer cell lines harboring PIK3CA activating mutations to WEHI-539 in culture (PMID: 27974663). | 27974663 |
| PIK3CA act mut | breast cancer | predicted - sensitive | mTOR Inhibitor | Torin 1 + WEHI-539 | Preclinical - Cell culture | Actionable | In a preclinical study, the ATP-competitive mTORC1/2 inhibitor Torin1 sensitized breast cancer cell lines harboring PIK3CA activating mutations to WEHI-539 in culture (PMID: 27974663). | 27974663 |
| PIK3CA act mut | breast cancer | predicted - sensitive | mTOR Inhibitor | Sapanisertib + WEHI-539 | Preclinical - Cell culture | Actionable | In a preclinical study, the ATP-competitive mTORC1/2 inhibitor Sapanisertib (MLN0128) sensitized breast cancer cell lines harboring PIK3CA activating mutations to WEHI-539 in culture (PMID: 27974663). | 27974663 |
| PIK3CA act mut | breast cancer | predicted - sensitive | mTOR Inhibitor | Vistusertib + WEHI-539 | Preclinical - Cell culture | Actionable | In a preclinical study, the ATP-competitive mTORC1/2 inhibitor Vistusertib (AZD2014) sensitized breast cancer cell lines harboring PIK3CA activating mutations to WEHI-539 in culture (PMID: 27974663). | 27974663 |
| PIK3CA act mut | triple-receptor negative breast cancer | predicted - sensitive | mTORC1 Inhibitor | Bevacizumab + Doxorubicin + Everolimus | Phase I | Actionable | In a Phase I trial, triple-receptor negative breast cancer patients, including those with PIK3CA activating mutations, demonstrated an overall response rate of 21% (11/52) and clinical benefit rate of 40% (21/52) when treated with a combination of Avastin (bevacizumab), Adriamycin (doxorubicin), and either Afinitor (everolimus) or Torisel (temsirolimus) (PMID: 27893038). | 27893038 |
| PIK3CA act mut | triple-receptor negative breast cancer | predicted - sensitive | mTORC1 Inhibitor | Bevacizumab + Doxorubicin + Temsirolimus | Phase I | Actionable | In a Phase I trial, triple-receptor negative breast cancer patients, including those with PIK3CA activating mutations, demonstrated an overall response rate of 21% (11/52) and clinical benefit rate of 40% (21/52) when treated with a combination of Avastin (bevacizumab), Adriamycin (doxorubicin), and either Afinitor (everolimus) or Torisel (temsirolimus) (PMID: 27893038). | 27893038 |
| PIK3CA act mut | head and neck squamous cell carcinoma | predicted - sensitive | mTOR Inhibitor PI3K Inhibitor (Pan) | AZD8055 + Cetuximab | Preclinical - Pdx | Actionable | In a preclinical study, two head and neck squamous cell carcinoma patient-derived xenograft (PDX) models harboring a PIK3CA activating mutation demonstrated greater delayed tumor growth when treated with a combination of AZD8055 and Erbitux (cetuximab) compared to either agent alone (PMID: 28446642). | 28446642 |
| PIK3CA act mut | Advanced Solid Tumor | conflicting | PIK3CA inhibitor | Taselisib | Phase II | Actionable | In a Phase II trial (MATCH), Taselisib (GDC-0032) treatment resulted in limited efficacy in heavily pretreated patients with advanced solid tumors harboring PIK3CA activating mutations, with an objective response rate of 0% (0/61) after a median follow-up of 35.7 months, stable disease in 52% (32/61), a median progression-free survival of 3.1 months, and a median overall survival of 7.2 months (PMID: 35138919; NCT02465060). | 35138919 |
| PIK3CA act mut | breast cancer | sensitive | PIK3CA inhibitor | Copanlisib | Phase I | Actionable | In a Phase I clinical trial, treatment with Aliqopa (copanlisib) resulted in partial response in one and stable disease in another patient with breast cancer harboring activating PIK3CA mutations (PMID: 27672108; NCT00962611). | 27672108 |
| PIK3CA act mut | lung squamous cell carcinoma | predicted - sensitive | PI3K Inhibitor (Pan) | Buparlisib | Preclinical - Pdx | Actionable | In a preclinical study, Buparlisib (BKM120) treatment resulted in inhibition of AKT and S6 phosphorylation and durable responses in 4/5 lung squamous cell carcinoma patient-derived xenograft (PDX) models harboring PIK3CA E545K or E542K mutations, 3 that also had PIK3CA amplification and 1 with PTEN loss (PMID: 30093452). | 30093452 |
| PIK3CA act mut | lung squamous cell carcinoma | predicted - sensitive | PIK3CA inhibitor | Alpelisib | Preclinical - Pdx | Actionable | In a preclinical study, Alpelisib (BYL719) treatment resulted in responses in multiple lung squamous cell carcinoma patient-derived xenograft (PDX) models harboring PIK3CA E545K or E542K mutations, including models with PIK3CA amplification or PTEN loss (PMID: 30093452). | 30093452 |
| PIK3CA act mut | lung non-small cell carcinoma | predicted - resistant | Osimertinib | Case Reports/Case Series | Actionable | In a retrospective analysis, activating PIK3CA mutations were identified in 6 of 100 patients with non-small cell lung cancer at treatment discontinuation of Tagrisso (osimertinib) (PMID: 31839416). | 31839416 | |
| PIK3CA act mut | triple-receptor negative breast cancer | predicted - sensitive | Akt Inhibitor (Pan) | Capivasertib + Paclitaxel | Phase II | Actionable | In a Phase II trial (PAKT), addition of Capivasertib (AZD5363) to Taxol (paclitaxel) as first-line therapy significantly improved median progression-free survival (9.3 vs 3.7 months, HR=0.30, p=0.01) and reduced risk (66%, HR=0.34, p=0.04) compared to Taxol (paclitaxel) alone in patients with metastatic triple-negative breast cancer harboring activating mutations in AKT1 (E17K, n=1) or PIK3CA (n=17), or inactivating mutations or gene loss in PTEN (n=13) (PMID: 31841354; NCT02423603). | 31841354 |
| PIK3CA act mut | estrogen-receptor positive breast cancer | predicted - sensitive | PIK3CA inhibitor | Palbociclib + Taselisib | Phase I | Actionable | In a Phase Ib trial (PIPA), the combination of Ibrance (palbociclib) with Taselisib (GDC-0032) was well tolerated in estrogen-receptor negative breast cancer patients harboring PIK3CA activating mutations and resulted in an objective response rate of 10% (1/10), a clinical benefit rate of 30% (4/10), and a median progression-free survival of 3.6 months (PMID: 32958578; NCT02389842). | 32958578 |
| PIK3CA act mut | Advanced Solid Tumor | predicted - sensitive | PIK3CA inhibitor | Palbociclib + Taselisib | Phase I | Actionable | In a Phase Ib trial (PIPA), the combination of Ibrance (palbociclib) with Taselisib (GDC-0032) was well tolerated in patients with advanced solid tumors harboring PIK3CA activating mutations and resulted in an objective response rate of 0% (0/12), a clinical benefit rate of 16.7% (2/12), and a median progression-free survival of 3.8 months (PMID: 32958578; NCT02389842). | 32958578 |
| PIK3CA act mut | triple-receptor negative breast cancer | no benefit | Akt Inhibitor (Pan) | Ipatasertib + Paclitaxel | Phase II | Actionable | In a Phase II trial (LOTUS), Ipatasertib (GDC-0068) in combination with Abraxane (paclitaxel) resulted a median progression free survival of 6.2 vs 4.9 months with placebo in triple-receptor negative breast cancer patients harboring activating mutations in PIK3CA or AKT1, or inactivating mutations in PTEN (PMID: 28800861; NCT02162719). | 28800861 |
| PIK3CA act mut | triple-receptor negative breast cancer | no benefit | Akt Inhibitor (Pan) | Ipatasertib + Paclitaxel | Phase III | Actionable | In a Phase III trial (IPATunity 130), the addition of Ipatasertib (GDC-0068) to treatment with Abraxane (paclitaxel) did not result in improved progression-free survival in patients with triple-negative breast cancer harboring PIK3CA and/or AKT activating mutations or PTEN alterations, with a median PFS of 7.4 months with Ipatasertib (GDC-0068) plus Abraxane (paclitaxel) vs. 6.1 months with placebo plus Abraxane (paclitaxel) (SABCS Meeting 2020, Abstract GS3-04; NCT03337724). | detail... |
| PIK3CA act mut | Advanced Solid Tumor | no benefit | Akt Inhibitor (Pan) | TAS-117 | Phase II | Actionable | In a Phase II trial, TAS-117 treatment in advanced solid tumor patients with PIK3CA activating mutations (n=12) or AKT1 E17K (n=1) refractory to standard treatment had minimal activity, and led to an overall response rate of 8% (1/13), disease control rate of 23% (3/13), median progression-free survival of 1.4 months (mo), and a median overall survival of 4.8 mo, however due to poor accrual and lack of durable response to TAS-117 early termination of study was recommended (PMID: 33723724; NCT03017521). | 33723724 |
| PIK3CA act mut | Advanced Solid Tumor | predicted - sensitive | mTOR Inhibitor PI3K Inhibitor (Pan) | LY3023414 + Prexasertib | Phase I | Actionable | In a Phase Ib trial, the combination therapy of Samotolisib (LY3023414) and Prexasertib (LY2606368) resulted in an overall response rate of 13.3% (2/15; 2 partial responses) in patients with an advanced solid tumor harboring a PIK3CA activating mutation of either H1047R, H1047L, E542K, or E545K (PMID: 33495309; NCT02124148). | 33495309 |
| PIK3CA act mut | endometrial cancer | no benefit | mTOR Inhibitor PI3K Inhibitor (Pan) | LY3023414 | Phase II | Actionable | In a Phase II trial, patients with advanced endometrial cancer harboring a PI3K pathway mutation, including PIK3CA activating mutations, demonstrated only a modest clinical benefit with an overall response rate of 16% (4/25), a clinical benefit rate of 28% (7/25) at 12 weeks, a progression-free survival of 2.5 months, and overall survival of 9.2 months when treated with LY3023414 (PMID: 31880826; NCT01775072). | 31880826 |
| PIK3CA act mut | Her2-receptor negative breast cancer | predicted - sensitive | PIK3CA inhibitor | Alpelisib + Nab-paclitaxel | Clinical Study - Cohort | Actionable | In a Phase I/II trial, Piqray (Alpelisib) and Abraxane (nab-paclitaxel) combination treatment resulted in improved clinical benefit rate (100% vs 68%; OR=1.47, P=0.013) and median progression-free survival (11.9 vs 7.5 mo.; HR=0.44, P=0.027) and longer median overall survival (26.7 vs. 14.9 mo.; HR=0.59, P=0.19) in patients with ERBB2 (HER2)-negative metastatic breast cancer harboring activating PIK3CA mutations compared to patients without PIK3CA mutations (PMID: 33602685; NCT02379247). | 33602685 |
| PIK3CA act mut | Advanced Solid Tumor | predicted - sensitive | Akt Inhibitor (Pan) | Docetaxel + Ipatasertib | Phase I | Actionable | In a Phase Ib trial, the combination of Ipatasertib (GDC-0068) and Taxotere (docetaxel) resulted in an objective response rate (ORR) of 7.7% (2/26, partial responses) in patients with advanced solid tumors (n=26), and ORR was proportionally higher in patients harboring activating PIK3CA mutations (1/4) compared to patients without PIK3CA activating mutations (1/22) (PMID: 32205017; NCT01362374). | 32205017 |
| PIK3CA act mut | Advanced Solid Tumor | predicted - sensitive | Akt Inhibitor (Pan) | Fluorouracil + Ipatasertib + Leucovorin + Oxaliplatin | Phase I | Actionable | In a Phase Ib trial, the combination of Ipatasertib (GDC-0068) and mFOLFOX6 resulted in an objective response rate (ORR) of 6.1% (2/33, partial responses) in patients with advanced solid tumors (n=33), and ORR was proportionally higher in patients harboring activating PIK3CA mutations (1/4) compared to in patients without PIK3CA activating mutations (1/29) (PMID: 32205017; NCT01362374). | 32205017 |
| PIK3CA act mut | castration-resistant prostate carcinoma | predicted - sensitive | mTOR Inhibitor | CC-115 + Enzalutamide | Phase I | Actionable | In a Phase Ib trial, combination of Xtandi (enzalutamide) and CC-115 was safe and resulted in a PSA reduction >= 50% (PSA50) in 80% and >=90% (PSA90) in 58% of patients with metastatic castration-resistant prostate cancer at 12 weeks, patients harboring PIK3CA activating mutations or TSC1/2 loss (n=16) achieved superior PSA50, PSA90, and median time on treatment (94%, 63%, 57 wks) compared to PI3K pathway wild-type (n=24) patients (71%, 54%, 44 wks) (Ann Oncol (2021) 32 (suppl_5): S626-S677; NCT02833883). | detail... |
| PIK3CA act mut | Advanced Solid Tumor | predicted - sensitive | PIK3CA inhibitor | RLY-2608 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, RLY-2608 treatment led to inhibition of cell viability in a panel of cancer cell lines harboring PIK3CA hotspot mutations, and led to tumor regression or stasis in cell line xenograft models (Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P251). | detail... |