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

Koji Fukuda; Shinji Takeuchi; Sachiko Arai; Shigeki Nanjo; Shigeki Sato; Hiroshi Kotani; Kenji Kita; Akihiro Nishiyama; Hiroyuki Sakaguchi; Koshiro Ohtsubo; Seiji Yano

doi:10.1016/j.xcrm.2024.101578

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

Cell Rep Med. 2024 Jun 18;5(6):101578. doi: 10.1016/j.xcrm.2024.101578. Epub 2024 May 21.

Authors

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.

MeSH terms

Animals
Apoptosis* / drug effects
Apoptosis* / genetics
Carcinoma, Non-Small-Cell Lung* / drug therapy
Carcinoma, Non-Small-Cell Lung* / genetics
Carcinoma, Non-Small-Cell Lung* / pathology
Cell Cycle Proteins* / antagonists & inhibitors
Cell Cycle Proteins* / genetics
Cell Cycle Proteins* / metabolism
Cell Line, Tumor
Humans
Lung Neoplasms* / drug therapy
Lung Neoplasms* / genetics
Lung Neoplasms* / pathology
Mice
Mice, Nude
Mutation* / genetics
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use
Protein-Tyrosine Kinases* / antagonists & inhibitors
Protein-Tyrosine Kinases* / genetics
Protein-Tyrosine Kinases* / metabolism
Proto-Oncogene Proteins p21(ras)* / antagonists & inhibitors
Proto-Oncogene Proteins p21(ras)* / genetics
Proto-Oncogene Proteins p21(ras)* / metabolism
Tumor Suppressor Protein p53* / genetics
Tumor Suppressor Protein p53* / metabolism
Xenograft Model Antitumor Assays

Substances

WEE1 protein, human
Protein-Tyrosine Kinases
Tumor Suppressor Protein p53
Proto-Oncogene Proteins p21(ras)
Cell Cycle Proteins
KRAS protein, human
TP53 protein, human
Protein Kinase Inhibitors