Genetic alterations in the PI3K/AKT pathway and baseline AKT activity define AKT inhibitor sensitivity in breast cancer patient-derived xenografts.

Abstract

PURPOSE:AZD5363/capivasertib is a pan-AKT catalytic inhibitor with promising activity in combination with paclitaxel in triple negative metastatic breast cancer harboring PI3K/AKT-pathway alterations and in estrogen receptor-positive breast cancer in combination with fulvestrant. Here, we aimed to identify response biomarkers and uncover mechanisms of resistance to AZD5363 and its combination with paclitaxel. EXPERIMENTAL DESIGN:Genetic and proteomic markers were analyzed in HER2-negative patient-derived xenografts (PDXs) and patient samples, and correlated to AZD5363 sensitivity as single agent and in combination with paclitaxel. RESULTS:Four PDX were derived from patients receiving AZD5363 in the clinic which exhibited concordant treatment response. Mutations in PIK3CA/AKT1 and absence of mTORC1-activating alterations, e.g. in MTOR or TSC1, were associated with sensitivity to AZD5363 monotherapy. Interestingly, excluding PTEN from the composite biomarker increased its accuracy from 64 to 89%. Moreover, resistant PDXs exhibited low baseline pAKT S473 and residual pS6 S235 upon treatment, suggesting that parallel pathways bypass AKT/S6K1 signaling in these models. We identified two mechanisms of acquired resistance to AZD5363: cyclin D1 overexpression and loss of AKT1 p.E17K. CONCLUSIONS:This study provides insight into putative predictive biomarkers of response and acquired resistance to AZD5363 in HER2-negative metastatic breast cancer.