The Next-Generation Oral Selective Estrogen Receptor Degrader Camizestrant (AZD9833) Suppresses ER+ Breast Cancer Growth and Overcomes Endocrine and CDK4/6 Inhibitor Resistance.

Autor:	Lawson M; The Discovery Centre, Biomedical Campus, AstraZeneca, Cambridge, United Kingdom., Cureton N; The Discovery Centre, Biomedical Campus, AstraZeneca, Cambridge, United Kingdom., Ros S; The Discovery Centre, Biomedical Campus, AstraZeneca, Cambridge, United Kingdom., Cheraghchi-Bashi A; The Discovery Centre, Biomedical Campus, AstraZeneca, Cambridge, United Kingdom., Urosevic J; The Discovery Centre, Biomedical Campus, AstraZeneca, Cambridge, United Kingdom., D'Arcy S; The Discovery Centre, Biomedical Campus, AstraZeneca, Cambridge, United Kingdom., Delpuech O; The Discovery Centre, Biomedical Campus, AstraZeneca, Cambridge, United Kingdom., DuPont M; Research and Early Development, Oncology R&D, AstraZeneca, Waltham, Massachusetts., Fisher DI; Discovery Sciences, Biopharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom., Gangl ET; Research and Early Development, Oncology R&D, AstraZeneca, Waltham, Massachusetts., Lewis H; The Discovery Centre, Biomedical Campus, AstraZeneca, Cambridge, United Kingdom., Trueman D; The Discovery Centre, Biomedical Campus, AstraZeneca, Cambridge, United Kingdom., Wali N; The Discovery Centre, Biomedical Campus, AstraZeneca, Cambridge, United Kingdom., Williamson SC; The Discovery Centre, Biomedical Campus, AstraZeneca, Cambridge, United Kingdom., Moss J; The Discovery Centre, Biomedical Campus, AstraZeneca, Cambridge, United Kingdom., Montaudon E; Institut Curie, Paris, France., Derrien H; Institut Curie, Paris, France., Marangoni E; Institut Curie, Paris, France., Miragaia RJ; Oncology Data Science, Oncology R&D, AstraZeneca, Cambridge, United Kingdom., Gagrica S; The Discovery Centre, Biomedical Campus, AstraZeneca, Cambridge, United Kingdom., Morentin-Gutierrez P; The Discovery Centre, Biomedical Campus, AstraZeneca, Cambridge, United Kingdom., Moss TA; The Discovery Centre, Biomedical Campus, AstraZeneca, Cambridge, United Kingdom., Maglennon G; Clinical Pharmacology and Safety Sciences, Biopharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom., Sutton D; The Discovery Centre, Biomedical Campus, AstraZeneca, Cambridge, United Kingdom., Polanski R; Discovery Sciences, Biopharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom., Rosen A; Research and Early Development, Oncology R&D, AstraZeneca, Waltham, Massachusetts., Cairns J; Discovery Sciences, Biopharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom., Zhang P; The Discovery Centre, Biomedical Campus, AstraZeneca, Cambridge, United Kingdom., Sánchez-Guixé M; Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain., Serra V; Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain., Critchlow SE; The Discovery Centre, Biomedical Campus, AstraZeneca, Cambridge, United Kingdom., Scott JS; The Discovery Centre, Biomedical Campus, AstraZeneca, Cambridge, United Kingdom., Lindemann JPO; The Discovery Centre, Biomedical Campus, AstraZeneca, Cambridge, United Kingdom., Barry ST; The Discovery Centre, Biomedical Campus, AstraZeneca, Cambridge, United Kingdom., Klinowska T; Late Development, Oncology R&D, AstraZeneca, Cambridge, United Kingdom., Morrow CJ; The Discovery Centre, Biomedical Campus, AstraZeneca, Cambridge, United Kingdom., Carnevalli LS; The Discovery Centre, Biomedical Campus, AstraZeneca, Cambridge, United Kingdom.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2023 Dec 01; Vol. 83 (23), pp. 3989-4004.
DOI:	10.1158/0008-5472.CAN-23-0694
Abstrakt:	Oral selective estrogen receptor degraders (SERD) could become the backbone of endocrine therapy (ET) for estrogen receptor-positive (ER+) breast cancer, as they achieve greater inhibition of ER-driven cancers than current ETs and overcome key resistance mechanisms. In this study, we evaluated the preclinical pharmacology and efficacy of the next-generation oral SERD camizestrant (AZD9833) and assessed ER-co-targeting strategies by combining camizestrant with CDK4/6 inhibitors (CDK4/6i) and PI3K/AKT/mTOR-targeted therapy in models of progression on CDK4/6i and/or ET. Camizestrant demonstrated robust and selective ER degradation, modulated ER-regulated gene expression, and induced complete ER antagonism and significant antiproliferation activity in ESR1 wild-type (ESR1wt) and mutant (ESR1m) breast cancer cell lines and patient-derived xenograft (PDX) models. Camizestrant also delivered strong antitumor activity in fulvestrant-resistant ESR1wt and ESR1m PDX models. Evaluation of camizestrant in combination with CDK4/6i (palbociclib or abemaciclib) in CDK4/6-naive and -resistant models, as well as in combination with PI3Kαi (alpelisib), mTORi (everolimus), or AKTi (capivasertib), indicated that camizestrant was active with CDK4/6i or PI3K/AKT/mTORi and that antitumor activity was further increased by the triple combination. The response was observed independently of PI3K pathway mutation status. Overall, camizestrant shows strong and broad antitumor activity in ER+ breast cancer as a monotherapy and when combined with CDK4/6i and PI3K/AKT/mTORi. Significance: Camizestrant, a next-generation oral SERD, shows promise in preclinical models of ER+ breast cancer alone and in combination with CDK4/6 and PI3K/AKT/mTOR inhibitors to address endocrine resistance, a current barrier to treatment. (©2023 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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