下一代口服选择性雌激素受体降解剂卡米泽斯曲（AZD9833）抑制ER+乳腺癌生长并克服内分泌和CDK4/6抑制剂的耐药性。
The next-generation oral selective estrogen receptor degrader camizestrant (AZD9833) suppresses ER+ breast cancer growth and overcomes endocrine and CDK4/6 inhibitor resistance.
发表日期：2023 Sep 19
作者：
Mandy Lawson, Natalie Cureton, Susana Ros, Azadeh Cheraghchi-Bashi-Astaneh, Jelena Urosevic, Sophie D'Arcy, Oona Delpuech, Michelle DuPont, David I Fisher, Eric T Gangl, Hilary Lewis, Dawn Trueman, Neha Wali, Stuart Charles Williamson, Jennifer Moss, Elodie Montaudon, Héloïse Derrien, Elisabetta Marangoni, Ricardo J Miragaia, Sladjana Gagrica, Pablo Morentin Gutierrez, Thomas Moss, Gareth A Maglennon, Daniel Sutton, Radoslaw Polanski, Alan Rosen, Jonathan Cairns, Pei Zhang, Mònica Sánchez-Guixé, Violeta Serra, Susan E Critchlow, James S Scott, Justin P O Lindemann, Simon T Barry, Teresa Klinowska, Christopher J Morrow, Larissa S Carnevalli
来源：
CANCER RESEARCH
摘要：
口服选择性雌激素受体降解剂（SERDs）可能成为雌激素受体阳性乳腺癌内分泌治疗（ET）的基石，因为它们能够比目前的ET更好地抑制雌激素驱动的癌症，并克服关键的耐药机制。在本研究中，我们评估了下一代口服SERD卡米泽斯坦（AZD9833）的临床药理学和疗效，并结合CDK4/6抑制剂（CDK4/6i）和PI3K/AKT/mTOR靶向治疗，评估了ER共靶策略在CDK4/6i和/或ET进展模型中的应用。卡米泽斯坦在ER1野生型（ESR1wt）和突变型（ESR1m）乳腺癌细胞系和患者来源的异种移植瘤模型中表现出强大而选择性的ER降解效应，调控ER调控的基因表达，并诱导完全的ER拮抗作用和显著的抗增殖活性。卡米泽斯坦还在富勒维司汀耐药的ESR1wt和ESR1m异种移植瘤模型中展示了强大的抗肿瘤活性。卡米泽斯坦与CDK4/6i（帕博西利布或阿贝马西利布）以及PI3Kαi（阿帕替尼）、mTORi（依维莫司）或AKTi（卡匹肽曲）的组合评估显示，卡米泽斯坦与CDK4/6i或PI3K/AKT/mTORi具有活性，并且三联组合能进一步增加抗肿瘤活性。该反应不依赖于PI3K通路突变状态。总体而言，卡米泽斯坦作为单药在ER阳性乳腺癌中展示了强大而广泛的抗肿瘤活性，并且与CDK4/6i和PI3K/AKT/mTORi联合应用时，抗肿瘤活性进一步增加。
Oral selective estrogen receptor degraders (SERDs) 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 anti-proliferation activity in ESR1 wild-type (ESR1wt) and mutant (ESR1m) breast cancer cell lines and patient-derived xenograft (PDX) models. Camizestrant also delivered strong anti-tumor 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 anti-tumor activity was further increased by the triple combination. The response was observed independently of PI3K pathway mutation status. Overall, camizestrant shows strong and broad anti-tumor activity in ER+ breast cancer as a monotherapy and when combined with CDK4/6i and PI3K/AKT/mTORi.