Journal
CLINICAL CANCER RESEARCH
Volume 26, Issue 14, Pages 3720-3731Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-19-3324
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Funding
- AstraZeneca
- GHD-Pink program
- FERO Foundation
- Orozco Family
- Catalan Agency AGAUR [2017 SGR 540]
- Miguel Servet Program (ISCIII) [CP14/00228, CPII19/00033]
- Agencia de Gestio d'Ajuts Universitaris i de Recerca (AGAUR) [2015 FI_B 01075]
- Marie Slodowska-Curie Innovative Training Networks PhD fellowship [H2020-MSCA-ITN-2015_675392]
- Ministerio de Economia y Competitividad [FJCI-2015-25412]
- FI-AGAUR [2019 FI_B 01199]
- Fundacion Cientifica Asociacion Espanola Contra el Cancer [AECC_Postdoctoral17-1062]
- Cancer Research UK
- EU H2020 Network of Excellence (EuroCAN)
- NCI [CA16672]
- NIH [P30 CA008748, RO1CA190642-01]
- CDMRP grant [BC171535P1]
- Breast Cancer Research Foundation
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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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