Targeting WEE1 enhances the antitumor effect of KRAS-mutated non-small cell lung cancer harboring TP53 mutations

• DOI: 10.1016/j.xcrm.2024.101578
• Publication Date: 2024-05-21T15:04:33Z
• Authors: Koji Fukuda; Shinji Takeuchi; Sachiko Arai; Shigeki Nanjo; Shigeki Sato; Hiroshi Kotani; Kenji Kita; Akihiro Nishiyama; Hiroyuki Sakaguchi; Koshiro Ohtsubo; Seiji Yano
• Keywords: Wee1; CHEK1; Mitotic catastrophe; Synthetic Lethality

The clinical development of Kirsten rat sarcoma virus (KRAS)-G12C inhibitors for the treatment KRAS-mutant lung cancer is limited by presence co-mutations, intrinsic resistance, and emergence acquired resistance. Therefore, innovative strategies enhancing apoptosis in KRAS-mutated non-small cell (NSCLC) are urgently needed. Through CRISPR-Cas9 knockout screening using a library 746 crRNAs drug with custom 432 compounds, we discover that WEE1 kinase potent enhancers apoptosis, particularly NSCLC cells harboring TP53 mutations. Mechanistically, inhibition promotes G2/M transition reduces checkpoint 2 (CHK2) Rad51 expression DNA damage response (DDR) pathway, which associated repair double-strand breaks, leading to mitotic catastrophe. Notably, combined KRAS-G12C consistently suppresses tumor growth. Our results suggest targeting as promising therapeutic strategy