Genetic Alterations in the PI3K/AKT Pathway and Baseline AKT Activity Define AKT Inhibitor Sensitivity in Breast Cancer Patient-derived Xenografts.

Abstract

<h4>Purpose</h4>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.<h4>Experimental design</h4>Genetic and proteomic markers were analyzed in 28 HER2-negative patient-derived xenografts (PDXs) and in patient samples, and correlated to AZD5363 sensitivity as single agent and in combination with paclitaxel.<h4>Results</h4>Four PDX were derived from patients receiving AZD5363 in the clinic which exhibited concordant treatment response. Mutations in <i>PIK3CA</i>/<i>AKT1</i> and absence of mTOR complex 1 (mTORC1)-activating alterations, for example, in <i>MTOR</i> or <i>TSC1</i>, were associated with sensitivity to AZD5363 monotherapy. Interestingly, excluding <i>PTEN</i> 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 <i>AKT1</i> p.E17K.<h4>Conclusions</h4>This study provides insight into putative predictive biomarkers of response and acquired resistance to AZD5363 in HER2-negative metastatic breast cancer.