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

• Published in: Cell death & disease 2024-07, Vol.15 (7), p.551-13, Article 551
• Main Authors: Zhang, Jiahui, Liu, Xiaoli, Hou, Peng, Lv, Yang, Li, Gongfeng, Cao, Guozhen, Wang, Huogang, Lin, Wenchu
• Format: Article
• Language: English
• Subjects: 13/1; 13/2; 13/31; 13/89; 13/95; 14/19; 14/34; 14/35; 14/5; 14/63; 38; 38/77; 42; 631/67/1059; 631/67/1612; 631/80/82; 64/60; Animals; Antibodies; Aurora Kinase A - antagonists & inhibitors; Aurora Kinase A - metabolism; Azepines - pharmacology; Biochemistry; Biomedical and Life Sciences; BRCA1 protein; BRCA1 Protein - genetics; BRCA1 Protein - metabolism; Cell Biology; Cell Culture; Cell Cycle Proteins - metabolism; Cell death; Cell Line, Tumor; DNA repair; DNA Repair - drug effects; Female; Humans; Immunology; Life Sciences; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Mice; Mice, Nude; Myc protein; Polo-Like Kinase 1; Protein Serine-Threonine Kinases - metabolism; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Pteridines; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; Rad51 Recombinase - metabolism; Small cell lung carcinoma; Small Cell Lung Carcinoma - drug therapy; Small Cell Lung Carcinoma - genetics; Small Cell Lung Carcinoma - metabolism; Small Cell Lung Carcinoma - pathology; Xenograft Model Antitumor Assays
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-024-06950-w

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