Genetic Alterations in the PI3K/AKT Pathway and Baseline AKT Activity Define AKT Inhibitor Sensitivity in Breast Cancer Patient-derived Xenografts.
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Date
2020-07-15Author
Gris-Oliver, A
Palafox, M
Monserrat, L
Brasó-Maristany, F
Òdena, A
Sánchez-Guixé, M
Ibrahim, YH
Villacampa, G
Grueso, J
Parés, M
Guzmán, M
Rodríguez, O
Bruna, A
Hirst, CS
Barnicle, A
de Bruin, EC
Reddy, A
Schiavon, G
Arribas, J
Mills, GB
Caldas, C
Dienstmann, R
Prat, A
Nuciforo, P
Razavi, P
Scaltriti, M
Turner, NC
Saura, C
Davies, BR
Oliveira, M
Serra, V
Type
Journal Article
Metadata
Show full item recordAbstract
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 28 HER2-negative patient-derived xenografts (PDXs) and in 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 mTOR complex 1 (mTORC1)-activating alterations, for example, 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.
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Research team
Molecular Oncology
Preclinical Modelling of Paediatric Cancer Evolution
Language
eng
Date accepted
2020-03-24
License start date
2020-07
Citation
Clinical cancer research : an official journal of the American Association for Cancer Research, 2020, 26 (14), pp. 3720 - 3731
Publisher
AMER ASSOC CANCER RESEARCH