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

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. [Display omitted] •WEE1 inhibitors enhance apoptosis in KRAS-mutant NSCLC with TP53 mutations•WEE1 inhibition triggers G2/M transition and disrupts CHK2-mediated DNA repair•Combined KRAS-G12C and WEE1 inhibition suppresses tumor growth in mouse models Fukuda et al. show that combining WEE1 kinase and KRAS-G12C inhibitors nearly eradicates KRAS-mutant NSCLC with TP53 mutations in mouse models. This approach disrupts the DNA repair mechanisms of cancer cells, offering an innovative therapeutic strategy for this challenging cancer type.