PIK3CA

Overview

PIK3CA encodes the catalytic p110α subunit of class I phosphoinositide 3-kinase (PIK3CA), a central signaling enzyme in pathways that regulate cell growth, survival, metabolism, and proliferation. As a protein target, PIK3CA is especially important in oncology because activating mutations can drive aberrant PI3K/AKT signaling and contribute to tumor progression and therapy resistance.

In biomedical research, PIK3CA is frequently studied as a drug target for selective PIK3CA inhibition. This is particularly relevant in cancers such as cervical cancer and breast cancer, where mutant PIK3CA can create a dependency on PIK3CA signaling. Recent studies also place PIK3CA within broader pathway networks involving EGFR/SRC-mediated EMT, KRAS, MAPK1, PTGS2, and the PI3K/Akt signaling pathway, underscoring its role as a hub in oncogenic signaling.

Focus of Latest Publications

Recent research reveals PIK3CA as a critical oncogenic driver and therapeutic target across multiple cancer types. Activating PIK3CA mutations, particularly the hotspot variants E545K and H1047R, are among the most frequent genetic alterations in breast cancer and are also prevalent in cervical and lung cancers. Beyond somatic mutations, PIK3CA gains can also occur as somatic mosaic variants in PIK3CA-related overgrowth spectrum (PROS) disorders such as CLOVES syndrome, where segmental overgrowth and complex vascular malformations emerge, including potentially reversible renal vascular complications.

Selective PI3K inhibitors have emerged as a primary therapeutic strategy for PIK3CA-mutant tumors. The PI3Kα-selective inhibitors alpelisib, inavolisib, and CYH33 selectively suppress growth in PIK3CA-mutant cancer cells while showing minimal effects in PIK3CA wild-type tumors. These agents exhibit divergent signaling responses depending on the specific PIK3CA mutation subtype, with studies revealing distinct adaptations between E545K and H1047R variants. Notably, upon PI3Kα inhibition, tumors engage bypass signaling through the MAPK pathway, prompting investigation of combined PI3K and MAPK inhibition as a strategy to enhance therapeutic efficacy and overcome adaptive resistance.

Clinical and preclinical studies demonstrate synergistic benefits of combining PIK3CA-targeted therapies with other modalities. In PIK3CA-mutant cervical cancer, PI3Kα inhibitors potentiate antigen-specific T-cell immunotherapy, with drug pretreatment prior to immune cell exposure yielding maximal tumor cell killing. In estrogen receptor-positive breast cancer, alternative approaches including androgen receptor modulation show comparable efficacy to selective estrogen receptor degraders in models harboring PIK3CA mutations. Additionally, selective PI3K inhibitors combined with conventional endocrine therapies represent a strategy to overcome acquired tamoxifen resistance in metastatic disease.

Beyond targeted small molecules, diverse therapeutic approaches converge on PIK3CA inhibition. Plant-derived compounds and fungal metabolites with strong molecular docking affinity for PIK3CA protein have demonstrated antiproliferative activity in renal cell carcinoma and other solid tumors through PI3K/AKT pathway suppression. Finally, emerging liquid biopsy technologies enable highly sensitive and specific detection of PIK3CA point mutations in cell-free DNA from plasma, facilitating non-invasive mutation profiling at variant allele frequencies as low as 0.01%, which supports early cancer detection and personalized treatment selection in PIK3CA-driven malignancies.

Key Publications

• NEWJun TRERNA1-mediated acetylation represses ferroptosis of non-small cell lung cancer cells via the KAT6A/H3K23ac/TRIM24-PIK3CA pathway. (Human cell, 2026, PMID 42340519): "Therefore, TRIM24 acts as a transcriptional activator to activate the transcription of PIK3CA and inhibit ferroptosis."
• NEWJun Renal vein thrombosis as a reversible vascular renal complication of CLOVES syndrome: a case report. (CEN case reports, 2026, PMID 42334730): "CLOVES syndrome molecularly supported by a somatic mosaic PIK3CA variant, NM_006218.4:c.1634 A > C, p.Glu545Ala, detected in affected hypertrophic tissue."
• NEWJun Exploiting androgen receptor agonism as a treatment strategy in estrogen receptor-positive metastatic breast cancer. (NPJ breast cancer, 2026, PMID 42310300): "EP0062 displayed comparable antitumor efficacy to selective ER degraders (SERDs), including in PDXs with ESR1, PIK3CA, or PTEN mutations."
• Jun Comparative metabolomic profiling and potential bioactive marker discovery of three Clerodendrum species and their different plant parts. (Fitoterapia, 2026, PMID 42235855): "molecular docking verification confirmed that these ingredients exhibited favorable binding activities against core targets PIK3CA and AKT1."
• May (Phospho)proteomic Profiling Reveals Mutation-Specific Adaptive Signaling to PI3Kα Inhibition in PIK3CA Mutant Breast Epithelial Cells. (Journal of proteome research, 2026, PMID 42204977): "Upon PI3Kα inhibition with alpelisib, insulin engaged bypass signaling that partially counteracted downstream suppression."
• May Single-nucleotide variant profiling in liquid biopsy with RECO-Cas. (Science advances, 2026, PMID 42172311): "Using the assay, we detect KRAS, EGFR, and PIK3CA point mutations in cfDNA from clinical plasma samples, demonstrating high sensitivity (90.48%) and excellent specificity (100%)."
• Jun Fungal metabolite-based immunotherapy overcomes tumor-associated macrophage immunosuppression. (Cell reports. Medicine, 2026, PMID 42173096): "Mechanistically, IM502 primarily inhibits PI3Kγ and redirects STAT signaling from STAT3/6 to STAT1/2 dominance, thereby reversing TAM-mediated immunosuppression, substantially enhancing the abundance and functional quality of natural killer (NK) and T cells."
• Jun PIK3CA mutant cervical cancer is selectively suppressed by PI3Kα inhibition (Alpelisib/BYL-719 and Inavolisib/GDC-0077) and cooperates with HPV directed T cell therapy. (Neoplasia (New York, N.Y.), 2026, PMID 41980433): "Notably, YAP1 amplification is associated with poorer patient survival."
• Jun Metabolomics integrated with mass spectrometry imaging reveals geographic variation in chemical composition of Ophiopogon japonicus. (Journal of chromatography. A, 2026, PMID 41950855): "Molecular docking confirmed strong interactions between ZMD-specific compounds (e.g., ruscogenin) and lung-related targets (5-LO, PI3Kδ), supporting traditional respiratory uses and potential antitumor activity."
• May Multi-omics analysis reveals psoralen to suppresses renal cell carcinoma through the PI3K/AKT pathway. (Molecular and clinical oncology, 2026, PMID 41929235): "Molecular docking analysis and molecular dynamics simulations indicated a strong binding affinity and enhanced structural stability of the bound complexes between PIK3CA (PDB ID: 9B4T) and PSO."