Data from Targeting BCL2 overcomes resistance and augments response to aurora kinase B inhibition by AZD2811 in small cell lung cancer

• DOI: 10.1158/1078-0432.c.6721653.v3
• Publication Date: 2024-09-16T12:30:36Z
• Authors: Kavya Ramkumar; Azusa Tanimoto; Carminia M. Della...; C. Allison Stewart; Qi Wang; Li Shen; Robert J. Cardnell; Jing Wang; Urszula M. Polanska; Courtney Andersen; Jamal Saeh; J. Elizabeth Pease; Jon Travers; Giulia Fabbri; Carl M. Gay; Jelena Urosevic; Lauren A. Byers
• Keywords: Aurora kinase

<div>Abstract<p>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 response. AURKB inhibition exploits inherent genomic vulnerability SCLC a promising approach. Here, we identify response develop rational combinations with improve treatment efficacy. Experimental design: Selective inhibitor AZD2811 was profiled large panel lines (n=57) patient-derived xenograft (PDX) models. Proteomic transcriptomic profiles were analyzed candidate resistance. Effects on polyploidy, DNA damage apoptosis measured flow cytometry western blotting. Rational drug validated PDX Results: showed potent growth inhibitory activity subset SCLC, often characterized by, but not to, high cMYC expression. Importantly, BCL2 expression predicted independent status. AZD2811-induced suppressed levels, while combining significantly sensitized resistant <i>In vivo</i>, sustained tumor reduction regression achieved even intermittent dosing venetoclax, FDA approved inhibitor. Conclusions: overcomes intrinsic enhances sensitivity preclinical models.</p></div>