2. Academic Validation
  3. Targeting WEE1 enhances the antitumor effect of KRAS-mutated non-small cell lung cancer harboring TP53 mutations

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

Affiliations

  • 1 Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan; Nano Life Science Institute, Kanazawa University, Kanazawa, Japan. Electronic address: kfukuda@staff.kanazawa-u.ac.jp.
  • 2 Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan; Nano Life Science Institute, Kanazawa University, Kanazawa, Japan. Electronic address: takeuchi@staff.kanazawa-u.ac.jp.
  • 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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-10993
    99.97%, Wee1 Inhibitor