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

Abstract

G₁-S checkpoint loss contributes to carcinogenesis and increases reliance upon the G₂-M checkpoint for adaptation to stress and DNA repair, making G₂-M checkpoint inhibition a target for novel therapeutic development. AZD1775, an inhibitor against the critical G₂-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 <i>TP53</i> loss. Whether AZD1775 efficacy is modulated by other molecular contexts remains poorly understood. The tumor suppressor serine/threonine kinase 11 (<i>LKB1/STK11</i>) is one of the most frequently mutated genes in non-small cell lung cancer (NSCLC) and is commonly comutated with oncogenic <i>KRAS</i> mutations. We investigated the preclinical effects of AZD1775 in the context of <i>KRAS</i>/<i>LKB1</i> 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 <i>LKB1</i>-deficient NSCLC cells. <i>In vitro, LKB1</i> deficiency enhanced DNA damage and apoptosis in response to AZD1775 exposure compared with wild-type <i>LKB1</i> cells. In a genetically engineered mouse model of mutant <i>Kras</i> with concomitant loss of <i>Lkb1</i>, 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 <i>KRAS</i>/<i>LKB1</i> NSCLC. <i>Cancer Res; 77(17); 4663-72. ©2017 AACR</i>.