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

Autor:	Gris-Oliver A; Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain., Palafox M; Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain., Monserrat L; Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain., Brasó-Maristany F; Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer, Biomedical Research Institute (IDIBAPS), Barcelona, Spain., Òdena A; Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain., Sánchez-Guixé M; Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain., Ibrahim YH; Weil Cornell Medicine, New York, New York., Villacampa G; Oncology Data Science Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain., Grueso J; Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain., Parés M; Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain., Guzmán M; Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain., Rodríguez O; Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain., Bruna A; Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge., Hirst CS; Early Oncology, AstraZeneca, Cambridge, United Kingdom., Barnicle A; Early Oncology, AstraZeneca, Cambridge, United Kingdom., de Bruin EC; Early Oncology, AstraZeneca, Cambridge, United Kingdom., Reddy A; Early Oncology, AstraZeneca, Cambridge, United Kingdom., Schiavon G; Early Oncology, AstraZeneca, Cambridge, United Kingdom., Arribas J; Growth Factors Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.; Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Bellaterra, Spain.; Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain.; CIBERONC, Instituto de Salud Carlos III, Madrid, Spain., Mills GB; Department of Cell Development and Cancer Biology, Knight Cancer Institute, Oregon Health and Sciences University, Portland, Oregon.; Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Caldas C; Department of Oncology and Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, United Kingdom.; Cambridge Breast Unit, NIHR Cambridge Biomedical Research Centre and Cambridge Experimental Cancer Medicine Centre at Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom., Dienstmann R; Oncology Data Science Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain., Prat A; Translational Genomics and Targeted Therapeutics in Solid Tumors, August Pi i Sunyer, Biomedical Research Institute (IDIBAPS), Barcelona, Spain.; Department of Medical Oncology, Hospital Clínic de Barcelona, Spain.; SOLTI Breast Cancer Cooperative Group, Barcelona, Spain., Nuciforo P; CIBERONC, Instituto de Salud Carlos III, Madrid, Spain.; Molecular Oncology Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain., Razavi P; Department of Medicine and Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York., Scaltriti M; Department of Pathology and Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York., Turner NC; Institute of Cancer Research and Royal Marsden Hospital, Fulham Road, London, United Kingdom., Saura C; Department of Medical Oncology, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.; Breast Cancer and Melanoma Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain., Davies BR; Early Oncology, AstraZeneca, Cambridge, United Kingdom., Oliveira M; Department of Medical Oncology, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.; Breast Cancer and Melanoma Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain., Serra V; Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain. vserra@vhio.net.; CIBERONC, Instituto de Salud Carlos III, Madrid, Spain.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2020 Jul 15; Vol. 26 (14), pp. 3720-3731. Date of Electronic Publication: 2020 Mar 27.
DOI:	10.1158/1078-0432.CCR-19-3324
Abstrakt:	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. (©2020 American Association for Cancer Research.)
Databáze:	MEDLINE
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