Abstract 2817: An inhibitor to the WEE1 kinase has pre-clinical activity in mutant KRAS/LKB1-deficient non-small cell lung cancer
Authors: Richer Amanda L. , Cala Jacqueline M. , O’Brien Kelley , Carson Vashti M. , Whitsett Timothy G. , Inge Landon J. 
Published: July 2016

Abstract
Within eukaryotic cells, the G1/S and G2/M cell cycle checkpoints activate in response to intracellular or extracellular stress to prevent defects in DNA synthesis and mitosis. Deregulation of the cell cycle is a fundamental characteristic of cancer, with loss of the G1/S checkpoint playing an important role in carcinogenesis. Phenotypically, loss of the G1/S checkpoint within tumor cells results in increased reliance upon the G2/M checkpoint for adaptation to stress and DNA damage repair. This dependence has led to interest towards inhibition of the G2/M checkpoint for therapeutic treatment. Efforts have produced several clinically relevant compounds that target the regulatory proteins of the G2/M checkpoint. One of these compounds the WEE1 kinase inhibitor, AZD1775 displays favorable activity in a variety of pre-clinical tumor models in combination with DNA damaging agents and in particular, AZD1775 shows enhanced activity in tumor cells harboring inactivating mutations to p53. However, whether AZD1775 or other G2 checkpoint inhibitors have improved activity in the context of other mutations remains poorly understood. The tumor suppressor, LKB1 (STK11) is one of the most frequently mutated genes in non-small cell lung cancer (NSCLC) and is commonly co-mutated with oncogenic mutations to KRAS (mtKRAS). Functional studies have revealed that mtKRAS/LKB1-deficient (LKB1-) NSCLC cells display increased activation of the G2/M checkpoint and this characteristic of mtKRAS/LKB1- NSCLC has been proposed as a point for therapeutic intervention. Based upon the reported response of tumor cells to AZD1775, we investigated the pre-clinical effects of AZD1775 in mtKRAS/LKB1- NSCLC. Employing NSCLC cell lines, we find that AZD1775 has increased activity in mtKRAS/LKB1- cells in vitro. mtKRAS/LKB1- NSCLC cells display increased protein levels of markers of DNA damage (phosphorylated γ-H2AX) and apoptosis (cleaved PARP) and reduced cell viability with AZD1775 treatment, compared to mtKRAS NSCLC with functional LKB1. The effects of AZD1775 in mtKRAS/LKB1- NSCLC cells were enhanced in the presence of DNA damaging agents (radiation, cisplatin). Using a genetically-engineered mouse model of mtKRAS/LKB1- NSCLC, combined treatment of AZD1775 and cisplatin were found to increase overall survival, compared to cisplatin mono-therapy in vivo. Collectively, these findings suggest that application of AZD1775 with DNA damaging agents may have therapeutic efficacy in mtKRAS/LKB1- NSCLC, a genomic subgroup of lung cancer with no effective therapeutic regimens.
Citation Format: Amanda L. Richer, Jacqueline M. Cala, Kelley O’Brien, Vashti M. Carson, Timothy G. Whitsett, Landon J. Inge. An inhibitor to the WEE1 kinase has pre-clinical activity in mutant KRAS/LKB1-deficient non-small cell lung cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2817.