PIK3CA G1049R

Moreover, we show that in the H1047R mutant, the cavity, where the allosteric ligands STX-478 and RLY-2608 bind, is more accessible contrary to the WT. This study provides insights into the molecular mechanisms underlying activation of oncogenic PI3Kα by C-terminal mutations and represents a valuable resource for continued efforts in the development of mutant selective inhibitors as therapeutics.

P2, N=51, Recruiting, GOG Foundation | Not yet recruiting --> Recruiting

P2, N=51, Not yet recruiting, GOG Foundation | Trial completion date: Apr 2025 --> Apr 2026 | Initiation date: Apr 2022 --> Jan 2023 | Trial primary completion date: Aug 2024 --> Apr 2025

P2, N=11, Completed, NRG Oncology | Active, not recruiting --> Completed

P2, N=51, Not yet recruiting, GOG Foundation

Our study reveals the heterogeneity in PI3K-AKT-mTOR pathway among the breast cancer molecular subtypes in our cohort. Moreover, the number and specific sites of PIK3CA mutations have distinct prognostic impact.

Cohort A: HR+/HER2- pts receiving fulvestrant (FUL) alone (n = 124) or ALP/FUL (n = 111) in treatment line ≥2L were considered in survival analysis . This study validates the activity of ALP among a diverse real world population, showing pts with PIK3CA mutations have longer rwPFS on ALP/FUL than FUL alone . Pts with SOLAR1m were more likely to be treated with ALP- and tended to be treated in earlier line setting- than pts with OTHERm . No consistent effect in a small subset of pts with OTHERm treated with ALP was observed, but there is evidence that OTHERm may differ in their degree of PI3K activation, oncogenicity, and ALP sensitivity .

Further validation of these mutations using PIK3CA reporter assays led to the identification of several significant hypo-morphic signals in TP53 mutant samples. We defined this phenomenon as mutational mimicry (i.e. mutations in proteins mimicking those in established oncogenes) and we propose it as a tool for predicting tumor sensitivity/resistance to drugs.