PIK3CA / PI3K-alpha
PIK3CA is the most commonly mutated gene in hormone-driven breast cancer. Drugs against it work, but hitting it cleanly without raising blood sugar took years. This dossier gathers the 9 products (7 approved), 10 trials, 6 pathways and 6 resistance routes in the corpus that involve it, with external identifiers so it can be joined to UniProt, ChEMBL, Open Targets and the rest of biology.
Biology
PIK3CA encodes the catalytic subunit of PI3K; H1047R and E545K are the hotspots.
- HR+ breast cancer (~40%)
- Endometrial
- Head and neck
- Colorectal
Elsewhere: identifiers and databases
Built from HGNC, Ensembl, UniProt and ChEMBL idsHow common it is, by cancer
Full matrix →| Cancer | Prevalence | Measure | Note | Source |
|---|---|---|---|---|
| Endometrial cancer | 45-55% | Activating mutation | cBioPortal (TCGA) | |
| HR-positive / HER2-negative breast cancer | 35-40% | Activating mutation | cBioPortal (TCGA) | |
| Head and neck squamous cell carcinoma | 15-20% | Activating mutation | HPV+ enriched | cBioPortal (TCGA) |
| Colorectal cancer | 15-20% | Activating mutation | cBioPortal (TCGA) |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
Mutation hotspots and which drugs address them
| Residue | Kind | How common | What it does | Addressed by | Defeats | Source |
|---|---|---|---|---|---|---|
| E542K / E545K 545 | Activating | Helical hotspots; with H1047R they account for about 80% of PIK3CA mutations | Relieve inhibition by the p85 regulatory subunit. Drug response is similar across hotspots with alpelisib and inavolisib; mutant-selective inhibitors that spare wild-type p110alpha are in trials. | — | Samuels et al., Science 2004 | |
| H1047R / H1047L 1047 | Activating | The single most common PIK3CA allele | Kinase-domain hotspot that increases membrane association; the allele most mutant-selective programmes target first. | — | Samuels et al., Science 2004 |
Frequencies are quoted from the source on each row; a blank means no figure was sourced, not that it is rare. Domain boundaries are approximate. Sources for the map: Cancer Hotspots (MSK) · COSMIC: PIK3CA.
Products by modality and phase
Browse products →| Modality | Approved | Withdrawn or failed |
|---|---|---|
| Small molecule 8 | ||
| Degrader 1 | — |
Trials
Evidence ranking →| Trial | Phase | Status | Setting | Result | Products |
|---|---|---|---|---|---|
| ALASCCA NCT02647099 | 3 | Positive | Resected stage I-III rectal or stage II-III colon cancer with somatic PIK3CA (exon 9/20) or other PI3K-pathway alterations: aspirin 160 mg/day for 3 years vs placebo | 3-year recurrence HR 0.49 (PIK3CA hotspot) and 0.42 (other PI3K alterations). | |
| CAPItello-281 NCT04493853 | 3 | Positive | De novo metastatic hormone-sensitive prostate cancer with PTEN deficiency: abiraterone + capivasertib vs abiraterone + placebo | rPFS significantly improved (HR reported at presentation); approved 2026. | |
| COMPETE NCT03049189 | 3 | Positive | Progressive grade 1-2 SSTR-positive GEP-NETs: 177Lu-edotreotide vs everolimus | PFS 23.9 vs 14.1 months, HR 0.67. | |
| evERA NCT05306340 | 3 | Positive | ER+/HER2- advanced breast cancer after CDK4/6 inhibitor: giredestrant + everolimus vs standard endocrine therapy + everolimus | PFS HR 0.56 (ITT); HR 0.38 (ESR1-mutant). | |
| INAVO120 NCT04191499 | 3 | Positive | First-line PIK3CA-mutant HR+/HER2- advanced breast cancer relapsing on/after adjuvant endocrine therapy: inavolisib + palbociclib + fulvestrant vs placebo + palbociclib + fulvestrant | PFS 15.0 vs 7.3 months, HR 0.43; OS 34.0 vs 27.0 months, HR 0.67. | |
| LITESPARK-005 NCT04195750 | 3 | Positive | Advanced clear-cell RCC after PD-1/PD-L1 and VEGF-TKI: belzutifan vs everolimus | PFS HR 0.75; ORR 22.7% vs 3.5%; OS not significant. | |
| CAPItello-291 NCT04305496 | 3 | Positive | HR+/HER2- advanced breast cancer after aromatase inhibitor (± CDK4/6): capivasertib + fulvestrant vs placebo + fulvestrant | PFS HR 0.60 overall; HR 0.50 in AKT-pathway-altered. | |
| CLEAR (KEYNOTE-581) NCT02811861 | 3 | Positive | Untreated advanced clear-cell RCC: lenvatinib + pembrolizumab vs sunitinib (and lenvatinib + everolimus arm) | PFS 23.9 vs 9.2 months (HR 0.39); OS HR 0.79. | |
| SOLAR-1 NCT02437318 | 3 | Positive | HR+/HER2- advanced breast cancer after aromatase inhibitor: alpelisib + fulvestrant vs placebo + fulvestrant, by PIK3CA status | PFS 11.0 vs 5.7 months, HR 0.65 (PIK3CA-mutant). | |
| RADIANT-3 and RADIANT-4 NCT00510068 | 3 | Positive | Progressive pancreatic NETs (RADIANT-3, n=410) and lung/GI NETs (RADIANT-4, n=302): everolimus vs placebo | PFS HR 0.35 (pNET) and 0.48 (lung/GI). |
Resistance routes that involve this target
Unaddressed routes →PIK3CA mutation, PTEN loss, or AKT1 E17K sustain growth independent of ER.
- Capivasertib, inavolisib, alpelisib, everolimus, gedatolisib by genotype
More receptor, or mutations (F877L, T878A) that turn antagonists into agonists.
- AR degraders and N-terminal-domain inhibitors (trials); PSMA radioligand therapy
Truncated receptor lacking the ligand-binding domain is constitutively active and invisible to enzalutamide.
- Taxanes retain activity; N-terminal-domain inhibitors
RB1/TP53 loss enables transdifferentiation; AR-indifferent, DLL3-positive, PSMA-negative.
- Platinum-etoposide; DLL3 engagers (tarlatamab) and B7-H3 ADCs in trials
Reciprocal feedback between AR and PI3K pathways.
- Capivasertib + abiraterone (approved 2026 for PTEN-deficient disease)
GR drives an AR-like transcriptional programme under enzalutamide.
- GR antagonists (relacorilant tested in prostate cancer)
Pathways where it is a node
Pathway-to-drug matrix →- BCR::ABL1 (Philadelphia chromosome)Node: PI3K → AKT · 2 druggable nodes
Chronic myeloid leukaemia is caused by one broken gene: two chromosomes swap pieces and glue a kinase (ABL1) to a protein that forces it permanently on. Imatinib, the first drug to target it, turned a fatal disease into a manageable one, and later drugs cover the mutations that escape it.
Which nodes have drugs → - Cold tumours: immune deserts and exclusionNode: β-catenin, PTEN loss → no cDC1 · 6 druggable nodes
Tumours come in three immune weathers: inflamed (T cells inside, checkpoint drugs work), excluded (T cells stuck at the edge), and desert (no T cells at all). Most common cancers are excluded or desert, and turning them 'hot' is the central problem of immunotherapy.
Which nodes have drugs → - FGF / FGFR signallingNode: GAB1 → PI3K → AKT · 3 druggable nodes
Fibroblast growth factor receptors are growth antennas on the cell surface. Bladder cancer mutates FGFR3, bile duct cancer fuses FGFR2 to other genes, and stomach cancer overproduces FGFR2b; each has its own drug, and each brings a tell-tale side effect (high phosphate) because the same receptors control phosphate in the kidney.
Which nodes have drugs → - PI3K / AKT / mTORNode: PI3K (PIK3CA) · 3 druggable nodes
The cell's 'grow and survive' circuit. Growth signals from the surface switch on PI3K, which switches on AKT, which switches on mTOR, which builds proteins and blocks self-destruction.
Which nodes have drugs → - Receptor tyrosine kinase activationNode: PI3K → AKT · 5 druggable nodes
Growth-factor receptors are antennas on the cell surface that pair up when a signal lands and switch on the growth relays inside. Cancers mutate, multiply, or fuse these antennas so they broadcast 'grow' with no signal at all. Most targeted drugs, antibodies and ADCs start here.
Which nodes have drugs → - Resistance routes: how a blocked pathway comes backNode: 3 Downstream (PIK3CA, RB1) · 6 druggable nodes
When a drug blocks a cancer's engine, the cancer has five ways back: change the part the drug binds, make more of it, take a side road, switch to a different engine altogether, or stop letting the drug in. Knowing which route a tumour took decides the next drug.
Which nodes have drugs →
Companion diagnostics and assays
Assay registry →| Assay | Platform | Cut-off | Gates |
|---|---|---|---|
| FoundationOne CDx Foundation Medicine (Roche) · FDA CDx 2017 | NGS tissue | Per companion claim: EGFR, ALK, BRAF V600, ERBB2 amplification, KRAS wild-type, BRCA1/2 and HRR genes, PIK3CA, MET exon 14, RET, FGFR2 fusions, IDH1, NTRK fusions; MSI-high; TMB at least 10 mutations per megabase | |
| FoundationOne Liquid CDx Foundation Medicine (Roche) · FDA CDx 2020 | NGS plasma | Per companion claim: EGFR (osimertinib, erlotinib, gefitinib), ALK (alectinib), BRCA1/2 and ATM (olaparib, rucaparib), PIK3CA (alpelisib), FGFR3 (erdafitinib), NTRK and RET; negative plasma results reflex to tissue | |
| therascreen PIK3CA RGQ PCR Kit QIAGEN · FDA CDx 2019 | PCR | Mutation detected (alpelisib plus fulvestrant); plasma negative reflexes to tissue |
Preclinical models
All models →No model entry for this target yet; check the cancer entries on the models page.
Open questions
All open questions →No open questions recorded for this target yet. Suggest one.
Ideas and companies
Key papers and the live literature
Preprints →- Cancer genome landscapes: about 140 driver genes, and each tumour needs only a handful · Science 2013
Query for this target: (TITLE:"PIK3CA / PI3K-alpha" OR ABSTRACT:"PIK3CA / PI3K-alpha" OR TITLE:"PIK3CA" OR ABSTRACT:"PIK3CA") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about PIK3CA / PI3K-alpha, not a curated reading list.
Export
The dossier as machine-readable JSON: identifiers from HGNC, Ensembl, UniProt and ChEMBL, products with status, trials, pathways, hotspots, open questions and assays. The full entity record is in the open API at /api/v1/entities/pik3ca.json. Licence CC BY 4.0.