Over the past years, a key focus has been on identifying inhibitors against components of pathways that drive tumor cell proliferation, survival, and metastasis such as the PI3K/mTOR pathway, known to be implicated in many human cancers through various mechanisms, such as, somatic PIK3CA missense mutations that occur at high frequency in a number of common solid tumors including ~40% of ER+ breast cancer patients. Based on these findings, cancer-specific mutants of PI3Kα appear to be ideal targets for PI3Kα selective inhibitors such as alpelisib which is unique in its relative selectivity for the α-isoform and previously reported to be efficacious in PIK3CA mutant cancer models. Recently, using the ER-negative/HER2-positive/PIK3CA mutant HCC1954 breast cancer cell line, the PI3K β-sparing inhibitor taselisib has been described to have a dual mechanism of action, both blocking PI3K signaling and inducing a decrease in p110α protein levels. Here, we investigated whether such dual mechanism of action could be associated with PI3Kα selective inhibition in ER+/PIK3CA mutant breast cancer pre-clinical models specifically. In vitro, using the T47D ER+/PIK3CA mutant breast cancer cell line, alpelisib displays dual MoA by inhibiting p-Akt and inducing a decrease of p110a protein levels in a dose-dependent manner. This effect is observed upon 24 hours of compound treatment and is maintained for at least 96 hours upon treatment. Interestingly, for both alpelisib and taselisib, p110α degradation becomes more pronounced at concentrations which produce strong PI3K pathway inhibition (>80% p-Akt inhibition). In contrast to T47D cells, we do not observe p110α degradation upon 24 hours treatment in 4 additional ER+/PIK3CA mutant breast cancer cell lines tested, despite a dose-dependent and robust inhibition of the PI3K pathway, suggesting the effect might be specific to certain cell lines or restricted to certain PIK3CA mutations or might require longer compound treatment periods. In the EFM19 cells, the PI3K inhibition-mediated p110α degradation occurs upon minimum 48 hours treatment for both alpelisib and taselisib. In vitro, when alpelisib and taselisib are then compared at concentrations that equally inhibit the PI3K pathway and equally degrade p110α, both compounds display similar inhibitory effects on T47D and EFM19 cell proliferation and survival. In vivo, in an ER+/ PIK3CA mutant breast cancer patient derived xenograft (PTX) model, alpelisib and taselisib show comparable anti-tumoral efficacy when administered at doses that are equally well tolerated and induced comparable PI3K pathway modulation. Overall, the data demonstrate that in ER+/ PIK3CA mutant breast cancer pre-clinical models, selective PI3Kα inhibition can induce a dual mechanism of action and produces robust efficacy.

Citation Format: Christine Fritsch, Estelle Pfister, Nicolas Ebel, Daniel Guthy, Christian Schnell, Francesco Hofmann. Determination of the PI3Kα selective inhibitor alpelisib mechanism of action and efficacy in ER+/ PIK3CA mutant breast cancer preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3934.