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PubMed2005

Genetic alteration and expression of the phosphoinositol-3-kinase/Akt pathway genes PIK3CA and PIKE in human glioblastomas.

Glioblastomas frequently carry genetic alterations resulting in an aberrant activation of the phosphoinositol-3-kinase (Pi3k)/protein kinase B (Akt) signalling pathway, including most notably phosphatase and tensin homolog (PTEN) mutation, epidermal growth factor receptor (EGFR) amplification and rearrangement, as well as carboxyl-terminal modulator protein (CTMP) hypermethylation [Knobbe et al., (2004) Hypermethylation and transcriptional downregulation of the carboxyl-terminal modulator protein gene in glioblastomas. J Natl Cancer Institute, 96, 483-486]. Here, we investigated two further Pi3k/Akt pathway genes, namely PIK3CA (3q26.3) and phosphatidylinositol-3-kinase enhancer (PIKE) (CENTG1, 12q14), for genetic alteration and aberrant expression in a series of 97 primary glioblastomas. Single strand conformation polymorphism (SSCP) analysis of PIK3CA revealed somatic mutations in five tumours (5%). Twelve glioblastomas (12%) showed amplification of PIKE with invariable co-amplification of the adjacent CDK4 gene. All tumours with PIKE amplification as well as the vast majority of glioblastomas without amplification demonstrated increased expression of PIKE-A but not PIKE-S/L transcripts as compared with non-neoplastic brain tissue. Taken together, our data support an important role of PIK3CA and PIKE gene aberrations in the molecular pathogenesis of primary glioblastomas.

Adolescent↗

PubMed2005

Functional analysis of PIK3CA gene mutations in human colorectal cancer.

Mutations in the PIK3CA gene, which encodes the p110alpha catalytic subunit of phosphatidylinositol 3-kinase (PI3K), have been reported in human cancers, including colorectal cancer. Most of the mutations cluster at hotspots within the helical and kinase domains. Whereas H1047R, one of the hotspot mutants, is reported to have elevated lipid kinase activity, the functional consequences of other mutations have not been examined. In this study, we examined the effects of colon cancer-associated PIK3CA mutations on the lipid kinase activity in vitro, activation of the downstream targets Akt and p70S6K in vivo and NIH 3T3-transforming ability. Of eight mutations examined, all showed increased lipid kinase activity compared with wild-type p110alpha. All the mutants strongly activated Akt and p70S6K compared with wild-type p110alpha as determined by immunoblotting using phospho-specific antibodies. These mutants also induced morphologic changes, loss of contact inhibition, and anchorage-independent growth of NIH 3T3 cells. The hotspot mutations examined in this study, E542K, E545K, and H1047R, all had high enzymatic and transforming activities. These results show that almost all the colon cancer-associated PIK3CA mutations are functionally active so that they are likely to be involved in carcinogenesis.

Animals↗

PubMed2005

Breast cancer-associated PIK3CA mutations are oncogenic in mammary epithelial cells.

Activation of the phosphoinositide 3-kinase (PI3K) pathway has been implicated in the pathogenesis of a variety of cancers. Recently, mutations in the gene encoding the p110alpha catalytic subunit of PI3K (PIK3CA) have been identified in several human cancers. The mutations primarily result in single amino acid substitutions, with >85% of the mutations in either exon 9 or 20. Multiple studies have shown that these mutations are observed in 18% to 40% of breast cancers. However, the phenotypic effects of these PIK3CA mutations have not been examined in breast epithelial cells. Herein, we examine the activity of the two most common variants, E545K and H1047R, in the MCF-10A immortalized breast epithelial cell line. Both variants display higher PI3K activity than wild-type p110alpha yet remain sensitive to pharmacologic PI3K inhibition. In addition, expression of p110alpha mutants in mammary epithelial cells induces multiple phenotypic alterations characteristic of breast tumor cells, including anchorage-independent proliferation in soft agar, growth factor-independent proliferation, and protection from anoikis. Expression of these mutant p110alpha isoforms also confers increased resistance to paclitaxel and induces abnormal mammary acinar morphogenesis in three-dimensional basement membrane cultures. Together, these data support the notion that the cancer-associated mutations in PIK3CA may significantly contribute to breast cancer pathogenesis and represent attractive targets for therapeutic inhibition.

Breast Neoplasms↗

PubMed2026

Oncogenic PIK3CA enhances collective migration of mammary epithelial cells through ERK wave propagation.

Oncogenic mutations of the PIK3CA gene, which encodes the catalytic subunit of the phosphatidylinositol 3-kinase (PI3K) enhance cell migration via ERK (ERK1 and ERK2, also known as MAPK3 and MAPK1, respectively) activation. We analyzed the factors regulating collective cell migration (CCM) of genome-edited MCF10A cell lines carrying hotspot PIK3CA mutations E545K or H1047R. H1047R enhanced CCM and promoted the propagation of waves of ERK activity backwards from the wound edge, whereas E545K impaired both coordinated CCM and ERK activity wave formation. The distance traveled by ERK activity waves correlated with directional persistence of migrating cells. Inhibition of cell contractility stimulated ERK wave propagation and efficient CCM of E545K cells but impaired ERK waves and CCM in control cells. Impaired ERK wave propagation was consistently associated with non-linear cell-cell junctions and the loss of polarized distribution of actomyosin. Taken together, these analyses suggest that polarized actomyosin contractility and pulsatile ERK activation must be constrained in the territory of a phase diagram compatible with mechanotransduction of ERK waves across cell-cell junctions to achieve highly coordinated and efficient collective migration.

Cell Movement↗

PubMed2026

PIK3CA Polymorphisms in Cervical Cancer: Differential Impact of rs6443624 and rs141178472.

BACKGROUND: Cervical cancer remains a major cause of mortality in low- and middle-income settings. We assessed whether two PIK3CA single-nucleotide polymorphisms (SNPs) rs6443624 (A/C) and rs141178472 (C/T) are associated with disease risk, clinicopathological features, and survival. MATERIALS AND METHODS: In a prospective case control study at a tertiary center, 154 participants were enrolled (77 cases, 77 controls). Genomic DNA was isolated from FFPE cervical tumors (QIAamp DNA FFPE Tissue Kit) and genotyped using TaqMan allelic discrimination. Clinicopathological variables (FIGO stage, histology, grade, treatment, tumor-infiltrating lymphocytes [TILs]) were abstracted from records. Genotype distributions were compared by Pearson chi-square. Associations with clinicopathological features used chi-square/Fisher's exact as appropriate; ANOVA compared age across genotypes. Overall survival (OS) was estimated by Kaplan-Meier and compared with the log-rank test; mean OS with SE and 95% CI is reported. RESULTS: Cases were predominantly locally advanced at presentation and squamous histology; most were moderately differentiated. rs6443624 differed significantly between cases and controls (χ²=21.1, p<0.001), with CC over-represented in cases and CA less frequent. rs141178472 showed no significant case control difference (χ²=2.9, p=0.086). For OS, rs6443624 showed a significant genotype effect (log-rank χ²=23.45, p=0.001): AA had the poorest survival, CA the longest, CC intermediate. rs141178472 was not associated with OS (χ²=1.06, p=0.588). Genotype clinicopathological correlations for stage group, grade, TILs, and treatment were non-significant or inconsistent, with some comparisons limited by small sample sizes. CONCLUSION: The PIK3CA rs6443624 variant appears to influence both susceptibility and prognosis in cervical cancer, highlighting its potential as a biomarker for molecular risk stratification. Validation in larger, multi-center cohorts incorporating HPV/p16 assessment and extended follow-up is warranted to confirm its clinical relevance.

Humans↗

PubMed1994

Molecular cloning, cDNA sequence, and chromosomal localization of the human phosphatidylinositol 3-kinase p110 alpha (PIK3CA) gene.

Phosphatidylinositol (PI) 3-kinase is a heterodimeric enzyme comprising a 110-kDa catalytic subunit and an 85-kDa regulatory subunit that binds to tyrosine phosphopeptide sites linked directly or indirectly to receptors serving diverse signal functions. Knowledge of the structure and function of PI 3-kinase was greatly advanced by the purification, cDNA cloning, and subsequent expression of the bovine enzyme. Here the cloning of the cDNA for the human p110 alpha subunit of PI 3-kinase (PIK3CA), encoding a protein 99% identical to the bovine p110, and of its gene in YAC is described. The chromosomal localization of the gene for PIK3CA is shown to be at 3q21-qter as determined using somatic cell hybrids. In situ hybridization performed using Alu-PCR from the YAC DNA located the gene in 3q26.3.

Animals↗

PubMed2006

Mutation of the PIK3CA oncogene in human cancers.

It is now well established that cancer is a genetic disease and that somatic mutations of oncogenes and tumour suppressor genes are the initiators of the carcinogenic process. The phosphatidylinositol 3-kinase signalling pathway has previously been implicated in tumorigenesis, and evidence over the past year suggests a pivotal role for the phosphatidylinositol 3-kinase catalytic subunit, PIK3CA, in human cancers. In this review, we analyse recent reports describing PIK3CA mutations in a variety of human malignancies, and discuss their possible implications for diagnosis and therapy.

Class I Phosphatidylinositol 3-Kinases↗

PubMed2006

Cancer-specific mutations in PIK3CA are oncogenic in vivo.

The PIK3CA gene, coding for the catalytic subunit p110alpha of class IA phosphatidylinositol 3-kinases (PI3Ks), is frequently mutated in human cancer. Mutated p110alpha proteins show a gain of enzymatic function in vitro and are oncogenic in cell culture. Here, we show that three prevalent mutants of p110alpha, E542K, E545K, and H1047R, are oncogenic in vivo. They induce tumors in the chorioallantoic membrane of the chicken embryo and cause hemangiosarcomas in the animal. These tumors are marked by increased angiogenesis and an activation of the Akt pathway. The target of rapamycin inhibitor RAD001 blocks tumor growth induced by the H1047R p110alpha mutant. The in vivo oncogenicity of PIK3CA mutants in an avian species strongly suggests a critical role for these mutated proteins in human malignancies.

Animals↗

PubMed2004

Oncogenic mutations of PIK3CA in human cancers.

Phosphatidylinositol 3-kinases (PI3Ks) are important regulators of signaling pathways. To determine whether PI3Ks are genetically altered in human cancers, we recently analyzed the sequences of the PI3K gene family and discovered that one member, the PIK3CA gene encoding the p110alpha catalytic subunit, was frequently mutated in cancers of the colon, breast, brain and lung. The majority of mutations clustered near two positions within the PI3K helical or catalytic domains and at least one hotspot mutation appeared to increase kinase activity. PIK3CA represents one of the most highly mutated oncogenes identified in human cancers and may be a useful diagnostic and therapeutic target.

Class I Phosphatidylinositol 3-Kinases↗

PubMed2025

Recurrent FGFR2 and PIK3CA Mutations in Sialoblastoma.

PURPOSE: Sialoblastoma is an extremely rare low-grade malignant salivary gland neoplasm that presents at birth or early infancy and has heterogeneous clinical behavior. Due to its rarity, the molecular landscape remains incompletely characterized. We aimed to expand the current understanding of the genetic alterations in sialoblastoma through comprehensive molecular analysis. METHODS: Five sialoblastoma cases were retrieved from four institutional archives. Clinical and pathologic review was performed, and targeted next-generation sequencing was conducted using clinically validated panels. Copy number analysis was performed on four cases. RESULTS: The cohort included five patients with tumors located in parotid gland (n = 2), minor salivary glands (n = 2), and submandibular gland (n = 1). Four patients were diagnosed before 6 months of age. Histologically, all tumors showed solid organoid nests with primitive basaloid cells, dense fibrous stroma, and mitotic activity ranging from 8 to 25 per 10 high-power fields. Recurrent FGFR2 p.C382R variants were identified in 80% (4/5) of cases. Additional alterations were seen in FGFR2 p.C382R mutated tumors, including PIK3CA hotspot mutations in two cases (p.R88Q, p.R38H) and a truncating FGFR2 variant (p.L776Rfs) in one. The single tumor that lacked FGFR2 mutations harbored a CTNNB1 p.I35T variant and showed more favorable histologic features. Copy number analysis revealed recurrent whole-chromosome gains of chromosomes 8, 10, and 11. CONCLUSION: A distinct subset of sialoblastoma has FGFR2 p.C382R hotspot mutation as the predominant driver mutation. Tumors with this mutation tend to have solid growth pattern, aggressive histologic features, and clinical behavior. The identification of concurrent genomic alterations expands the molecular landscape of this rare tumor. The detection of alternative drivers, such as CTNNB1 hotspot mutations typical of basal cell adenoma, also suggests that a subset of sialoblastoma may represent other salivary gland tumors presenting in infancy.

Humans↗

PubMed2025

In-depth assessment of BRAF, NRAS, KRAS, EGFR, and PIK3CA mutations on cell-free DNA in the blood of melanoma patients receiving immune checkpoint inhibition.

INTRODUCTION: Circulating tumor DNA (ctDNA) holds promise for guiding immune checkpoint inhibitor (ICI) therapy and stratifying responders from non-responders. While tumor-informed ctDNA detection approaches are sensitive and mutation-inclusive, they require tumor tissue, which limits applicability in real-world settings. Conversely, tumor-agnostic methods often have limited genomic coverage. In this study, we evaluated a tumor-agnostic, broad-panel ctDNA assay in patients with advanced melanoma treated with ICI. METHODS: We conducted a prospective analysis of 241 longitudinal samples from 39 patients with unresectable stage III/IV melanoma using a SYSMEX targeted NGS panel covering 1,114 COSMIC mutations. Plasma samples were collected at baseline and during ICI therapy. The assay's sensitivity reached seven mutant molecules, corresponding to a 0.07% mutation allele frequency (MAF). ctDNA profiles were compared with matched tumor tissue and correlated with clinical features and survival. RESULTS: At baseline, ctDNA was detected in 64.5% of patients. Common mutations included BRAFV600E (43.8%) and NRASG12D (36.4%), followed by KRAS, EGFR, and PIK3CA variants. Overall tissue-plasma concordance was 51.6%, with more extended biopsy-plasma intervals associated with discordance (p = 0.0105). Notably, 12.2% of cases exhibited partial concordance, characterized by shared mutations and additional plasma-only alterations, underscoring the complementary value of blood-based profiling. Persistent or re-emerging ctDNA positivity post-therapy correlated with shorter progression-free survival (PFS, p = 0.003), while ctDNA-negative patients showed significantly improved outcomes. Patients that remained ctDNA-negative had significantly longer progression-free survival (median not reached) compared to those with persistent ctDNA positivity (median 3 months) or those converting to positive (median 7.5 months; p = 0.0073). Early NRAS and KRAS ctDNA levels strongly predicted poor response (p = 0.0069 and p = 0.028). The prognostic impact extended beyond canonical drivers, as non-hotspot variants also correlated with the outcome. Notably, even low-level ctDNA persistence (5-10 MM/mL) carried adverse prognostic implications (p = 0.0054). Concerning a shorter PFS, ctDNA positivity was also associated with elevated S100 levels (p = 0.047). Organ-specific mutation enrichment (e.g., KRASG12D in brain, EGFRG719A in lymph nodes) suggested possible metastatic tropism. CONCLUSION: Broad tumor-agnostic ctDNA analysis effectively identified clinically relevant mutations and predicted outcomes in ICI-treated melanoma patients. This approach enables tissue-independent and real-time ctDNA monitoring and may inform patient selection and therapeutic strategies in future interventional trials.

Humans↗

PubMed2026

Multitargeted comparative evaluation suggests 2-Aoeobenoxmide shows favourable in silico binding compared to Tucatinib against ERα, HER2, AKT1, EGFR, and PIK3CA in breast cancer.

Breast cancer is a leading cause of cancer-related morbidity and mortality globally, with the WHO reporting approximately 2.3 million new cases and 685,000 deaths annually. Drug resistance in breast cancer complicates treatment, with mutations in critical proteins contributing to therapy failure. Key oncogenic proteins involved in breast cancer progression-namely ERα (a ligand-activated nuclear receptor; PDB: 1A52) and the kinase domains of HER2 (PDB ID: 3PP0), AKT1 (PDB ID: 4EJN), EGFR (PDB ID: 4I23) and PIK3CA (PDB ID: 7R9V)-are pivotal in tumour progression and resistance mechanisms. Targeting these proteins using multitargeted therapeutic strategies may overcome resistance by disrupting key signalling pathways involved in cell proliferation, survival, and metastasis. Such combinatorial approaches promise to improve treatment efficacy and patient outcomes in cases of resistant breast cancer. In this study, we performed multitarget docking on prepared and validated protein structures against the ZINC natural compound library using HTVS, SP, and XP, with pose validation using MM-GBSA. We identified 2-Aoeobenoxmide (2-[1-(2-amino-2-oxo-ethoxy)-6-oxo-benzo[c]chromen-3-yl]oxyacetamide, ZINC134008) with docking and MM-GBSA scores ranging from -8.162 to -10.327 kcal/mol and from -47.18 to -57.62 kcal/mol, respectively, and compared the results with the FDA-approved drug Tucatinib, which exhibited lower binding affinity scores. We further evaluated pharmacokinetic properties using QikProp and electronic properties using DFT (Jaguar) and compared the descriptors of 2-Aoeobenoxmide with those of Tucatinib and with accepted reference ranges. We also performed the WaterMap for 5 nanoseconds (ns), computed various energies, interactions and hydration sites, and the comparison suggests that 2-Aoeobenoxmide shows more favourable hydration-site displacement and binding interactions than Tucatinib. Additionally, a 100 ns MD Simulation has resulted in far less deviation, fluctuations, and intermolecular interactions than Tucatinib, suggesting stable protein-ligand interactions, while the binding free energy and total complex energy computed across 0-1000 frames of the MD trajectories indicate that 2-Aoeobenoxmide is a promising in silico candidate. Importantly, because the entire study is computational, the findings should be interpreted as in silico hypotheses, and experimental validation through in vitro and in vivo assays is warranted before any clinical translation is considered.

Humans↗

PubMed2006