WEE1 Kinase Inhibitor AZD1775 Has Preclinical Efficacy in LKB1-Deficient Non-Small Cell Lung Cancer.

G-S checkpoint loss contributes to carcinogenesis and increases reliance upon the G-M checkpoint for adaptation to stress and DNA repair, making G-M checkpoint inhibition a target for novel therapeutic development. AZD1775, an inhibitor against the critical G-M checkpoint protein WEE1, is currently in clinical trials across a number of tumor types. AZD1775 and DNA-damaging agents have displayed favorable activity in several preclinical tumor models, often in the molecular context of loss. Whether AZD1775 efficacy is modulated by other molecular contexts remains poorly understood. The tumor suppressor serine/threonine kinase 11 () is one of the most frequently mutated genes in non-small cell lung cancer (NSCLC) and is commonly comutated with oncogenic mutations. We investigated the preclinical effects of AZD1775 in the context of / in NSCLC. Using NSCLC cell lines, we found that AZD1775 alone and in combination with DNA-damaging agents (e.g., cisplatin and radiation) decreased tumor cell viability in -deficient NSCLC cells. deficiency enhanced DNA damage and apoptosis in response to AZD1775 exposure compared with wild-type cells. In a genetically engineered mouse model of mutant with concomitant loss of , combined AZD1775 and cisplatin extended overall survival compared with cisplatin alone. Our data suggest that lack of phosphorylation of LKB1 by ATM was involved in AZD1775-mediated cytotoxicity. Collectively, these findings provide a clinical application for AZD1775 with DNA-damaging agents in / NSCLC. .