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Ref Type Journal Article
PMID (28652249)
Authors Richer AL, Cala JM, O'Brien K, Carson VM, Inge LJ, Whitsett TG
Title WEE1 Kinase Inhibitor AZD1775 Has Preclinical Efficacy in LKB1-Deficient Non-Small Cell Lung Cancer.
Journal Vol Issue Date Pages Journal Short Title
Cancer research 77 17 2017 Sep 01 4663-4672 Cancer Res
URL
Abstract Text 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 TP53 loss. Whether AZD1775 efficacy is modulated by other molecular contexts remains poorly understood. The tumor suppressor serine/threonine kinase 11 (LKB1/STK11) is one of the most frequently mutated genes in non-small cell lung cancer (NSCLC) and is commonly comutated with oncogenic KRAS mutations. We investigated the preclinical effects of AZD1775 in the context of KRAS/LKB1 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 LKB1-deficient NSCLC cells. In vitro, LKB1 deficiency enhanced DNA damage and apoptosis in response to AZD1775 exposure compared with wild-type LKB1 cells. In a genetically engineered mouse model of mutant Kras with concomitant loss of Lkb1, 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 KRAS/LKB1 NSCLC. Cancer Res; 77(17); 4663-72. ©2017 AACR.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References