We developed a sensitive, simple and rapid approach to detect the low-abundance PIK3CA (H1047R) mutation in real CRC specimens, providing an effective tool for guiding cancer targeted therapy.
Collectively, our data suggest that PF-04691502 exhibits potent anticancer activity in colorectal cancer by targeting both PIK3CA (H1047R) mutant CSCs and their derivatives.
The hotspot mutation H1047R in the oncogenic PIK3CA gene is frequently detected in breast cancer and enhances the enzymatic activity of PI3K to activate AKT/mTOR signaling cascade.
The aim of this study was to analyze the efficacy of PI3K/mTOR blockade in breast cancer brain metastases models.<b>Experimental Design:</b> The efficacy of GDC-0084 was evaluated in <i>PIK3CA</i>-mutant and <i>PIK3CA</i> wild-type breast cancer cell lines and the isogenic pairs of <i>PIK3CA</i> wild-type and mutant (H1047R/+) MCF10A cells <i>in vitro</i>.
PIK3CA mutations are seemingly the most common driver mutations in breast cancer with H1047R and E545K being the most common of these, accounting together for around 60% of all PIK3CA mutations and have promising therapeutic implications.
Active mutations of PI3K catalytic subunit PIK3CA (e.g., H1047R) and amplification of its homolog PIK3CB are observed in a large number of breast cancers.
This derivative showed low micromolar cytotoxic potency in all BrCa cell lines, a mild inhibition of the PI3Kα wild type and H1047R mutated enzyme and excellent pharmacokinetic parameters following oral and intraperitoneal administration at the designed dose of 10 mg/kg, with absence of in vivo phenotypic toxicity.
Formalin-fixed paraffin-embedded tumour specimens from 118 HER2-overexpressing breast cancer patients treated with radical local therapy and trastuzumab in adjuvant setting were used for the assessment of: (1) PIK3CA gene mutations (p.H1047R and p.E545K) by qPCR, and (2) expression of Ki-67, EGFR, MUC4, HER3 and PTEN by immunohistochemistry.
Formalin-fixed paraffin-embedded tumour specimens from 118 HER2-overexpressing breast cancer patients treated with radical local therapy and trastuzumab in adjuvant setting were used for the assessment of: (1) PIK3CA gene mutations (p.H1047R and p.E545K) by qPCR, and (2) expression of Ki-67, EGFR, MUC4, HER3 and PTEN by immunohistochemistry.
"Identification and Characterization of a Novel Constitutional PIK3CA Mutation in a Child Lacking the Typical Segmental Overgrowth of ""PIK3CA-Related Overgrowth Spectrum""."
Using a variety of physiologically relevant model systems with defined natural or knock-in PIK3CA mutations and/or PI3K hyperactivation, we show that PIK3CA-E545K mutations (found in ∼20% of PIK3CA-mutant breast cancers), but not PIK3CA-H1047R mutations (found in 55% of PIK3CA-mutant breast cancers), preferentially activate AKT1.
The results suggest PIK3CA H1047R mutant cells have a selective advantage in breast, contribute to breast cancer susceptibility, and drive tumor progression during breast carcinogenesis, even when present as only a subpopulation of tumor cells.