Table S1 from 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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posted on 2023-03-31, 21:45 authored by Albert Gris-Oliver, Marta Palafox, Laia Monserrat, Fara Brasó-Maristany, Andreu Òdena, Mònica Sánchez-Guixé, Yasir H. Ibrahim, Guillermo Villacampa, Judit Grueso, Mireia Parés, Marta Guzmán, Olga Rodríguez, Alejandra Bruna, Caroline S. Hirst, Alan Barnicle, Elza C. de Bruin, Avinash Reddy, Gaia Schiavon, Joaquín Arribas, Gordon B. Mills, Carlos Caldas, Rodrigo Dienstmann, Aleix Prat, Paolo Nuciforo, Pedram Razavi, Maurizio Scaltriti, Nicholas C. Turner, Cristina Saura, Barry R. Davies, Mafalda Oliveira, Violeta Serra

Percentage change in tumor volume in PDX per treatment and relevant PI3K/AKT/mTOR-pathway and TP53 mutations in PDX models

Funding

AGAUR

ISCIII

Marie Slodowska-Curie Innovative Training Networks PhD fellowship

Ministerio de Economía y Competitividad

Fundación Científica Asociación Española Contra el Cáncer

NCI

NIH

CDMRP

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ARTICLE ABSTRACT

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. 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. 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. 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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Keywords

Biomarkers Circulating tumor cells/DNA/exosomes Breast Cancer Cell Signaling Protein serine-threonine kinases Drug Mechanisms Cell cycle mechanisms of anticancer drug action Drug Resistance

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CC BY

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