癌症研究
极光抑制剂
细胞凋亡
极光激酶
肺癌
药理学
癌症
医学
生物
肿瘤科
细胞周期
内科学
生物化学
作者
Kavya Ramkumar,Azusa Tanimoto,Carminia M. Della Corte,C. Allison Stewart,Qi Wang,Ли Шен,Robert J. Cardnell,Jing Wang,Urszula M. Polanska,Courtney L. Andersen,Jamal C. Saeh,J. Elizabeth Pease,Jon Travers,Giulia Fabbri,Carl M. Gay,Jelena Urosevic,Lauren A. Byers
标识
DOI:10.1158/1078-0432.ccr-23-0375
摘要
Abstract Purpose: Therapeutic resistance to frontline therapy develops rapidly in small cell lung cancer (SCLC). Treatment options are also limited by the lack of targetable driver mutations. Therefore, there is an unmet need for developing better therapeutic strategies and biomarkers of response. Aurora kinase B (AURKB) inhibition exploits an inherent genomic vulnerability in SCLC and is a promising therapeutic approach. Here, we identify biomarkers of response and develop rational combinations with AURKB inhibition to improve treatment efficacy. Experimental Design: Selective AURKB inhibitor AZD2811 was profiled in a large panel of SCLC cell lines (n = 57) and patient-derived xenograft (PDX) models. Proteomic and transcriptomic profiles were analyzed to identify candidate biomarkers of response and resistance. Effects on polyploidy, DNA damage, and apoptosis were measured by flow cytometry and Western blotting. Rational drug combinations were validated in SCLC cell lines and PDX models. Results: AZD2811 showed potent growth inhibitory activity in a subset of SCLC, often characterized by, but not limited to, high cMYC expression. Importantly, high BCL2 expression predicted resistance to AURKB inhibitor response in SCLC, independent of cMYC status. AZD2811-induced DNA damage and apoptosis were suppressed by high BCL2 levels, while combining AZD2811 with a BCL2 inhibitor significantly sensitized resistant models. In vivo, sustained tumor growth reduction and regression was achieved even with intermittent dosing of AZD2811 and venetoclax, an FDA-approved BCL2 inhibitor. Conclusions: BCL2 inhibition overcomes intrinsic resistance and enhances sensitivity to AURKB inhibition in SCLC preclinical models.
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