1. Academic Validation
  2. 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.
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抑制剂