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

  • Cell Rep Med. 2024 May 15:101578. doi: 10.1016/j.xcrm.2024.101578.
Koji Fukuda  1 ,  Shinji Takeuchi  2 ,  Sachiko Arai  3 ,  Shigeki Nanjo  4 ,  Shigeki Sato  5 ,  Hiroshi Kotani  5 ,  Kenji Kita  6 ,  Akihiro Nishiyama  5 ,  Hiroyuki Sakaguchi  5 ,  Koshiro Ohtsubo  5 ,  Seiji Yano  7
Affiliations
  • 1. Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan; Nano Life Science Institute, Kanazawa University, Kanazawa, Japan. Electronic address: [email protected].
  • 2. Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan; Nano Life Science Institute, Kanazawa University, Kanazawa, Japan. Electronic address: [email protected].
  • 3. Nano Life Science Institute, Kanazawa University, Kanazawa, Japan.
  • 4. Department of Respiratory Medicine, Faculty of Medicine, Institute of Medical, Pharmaceutical, and Health Sciences, Kanazawa University, Kanazawa, Japan.
  • 5. Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
  • 6. Central Research Resource Branch, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
  • 7. Nano Life Science Institute, Kanazawa University, Kanazawa, Japan; Department of Respiratory Medicine, Faculty of Medicine, Institute of Medical, Pharmaceutical, and Health Sciences, Kanazawa University, Kanazawa, Japan.
PMID: 38776912 DOI: 10.1016/j.xcrm.2024.101578
Abstract

The clinical development of Kirsten rat sarcoma virus (KRAS)-G12C inhibitors for the treatment of KRAS-mutant lung Cancer is limited by the presence of co-mutations, intrinsic resistance, and the emergence of acquired resistance. Therefore, innovative strategies for enhancing Apoptosis in KRAS-mutated non-small cell lung Cancer (NSCLC) are urgently needed. Through CRISPR-Cas9 knockout screening using a library of 746 crRNAs and drug screening with a custom library of 432 compounds, we discover that Wee1 kinase inhibitors are potent enhancers of Apoptosis, particularly in KRAS-mutant NSCLC cells harboring TP53 mutations. Mechanistically, Wee1 inhibition promotes G2/M transition and reduces checkpoint kinase 2 (Chk2) and RAD51 expression in the DNA damage response (DDR) pathway, which is associated with Apoptosis and the repair of DNA double-strand breaks, leading to mitotic catastrophe. Notably, the combined inhibition of KRAS-G12C and Wee1 consistently suppresses tumor growth. Our results suggest targeting Wee1 as a promising therapeutic strategy for KRAS-mutated NSCLC with TP53 mutations.

Keywords
CHK2; DNA damage response pathway; G12C; KRAS; Kirsten rat sarcoma; TP53; WEE1; azenosertib; non-small cell lung cancer; sotorasib.
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