BRCA1 orchestrates the response to BI-2536 and its combination with alisertib in MYC-driven small cell lung cancer

• DOI: 10.1038/s41419-024-06950-w
• Publication Date: 2024-07-31T20:04:53Z
• Authors: Jiahui Zhang; Xiaoli Liu; Peng Hou; Yang Lv; Gongfeng Li; Guozhen Cao; Huogang Wang; Wenchu Lin
• Keywords: PLK1; Mitotic catastrophe

Abstract PLK1 is currently at the forefront of mitotic research and has emerged as a potential target for small cell lung cancer (SCLC) therapy. However, factors influencing efficacy inhibitors remain unclear. Herein, BRCA1 was identified key factor affecting response SCLC cells to BI-2536. Targeting AURKA with alisertib, non-toxic concentration, reduced BI-2536-induced accumulation RAD51, leading DNA repair defects death in cells. In vivo experiments confirmed that combining BI-2536 alisertib impaired capacity significantly delayed tumor growth. Additionally, GSEA analysis loss- gain-of-function assays demonstrated MYC/MYCN signaling crucial determining sensitivity its combination alisertib. The study further revealed positive correlation between RAD51 expression / expression, negative IC 50 values Manipulating influenced restored MYC/MYCN-induced enhancement Our findings indicate MYC/MYCN-RAD51 axes govern This propose combined use novel therapeutic strategy treatment patients activation.