Enhancement Of Radiation Response In Kras Mutant Non-Small Cell Lung Cancer Cells With The M E K Inhibitor Gsk1120212

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Biomarkers that can select appropriate patient subsets for optimal treatment will likely improve personalized delivery of cancer treatment. While radiotherapy is a cornerstone for the management of non-metastatic lung cancers, there are no clinically useful biomarkers to help predict for radiation responsiveness and to help select drugs to enhance radiation sensitization in non-small cell lung cancer (NSCLC). KRAS mutations are found in 20%-30% of NSCLC and confer drug resistance. Drugs that target downstream pathways activated in KRAS mutant cells could enhance cytotoxic effects. The purpose of this study is to evaluate if the potent MEK1/2 inhibitor GSK1120212 can selectively enhance radiation response based on the genomic context in lung cancer cell lines. We selected a panel of NSCLC cell lines with or without KRAS mutations and tested their response to combinational treatment with radiation and MEK inhibitor via clonogenic survival assay. We found that GSK1120212 had no radiation enhancement effect in the three KRAS wild type (WT) cell lines tested. In contrast, in three KRAS mutant lung cancer cells, GSK1120212 dramatically reduced clonogenic survival to radiation treatment (radiation enhancement factor 1.2-1.9). We found that GSK1120212 selectively induced G1 cell cycle arrest through regulating the expression of several cell cycle regulation proteins, such as Cyclin B1, Cyclin E1 and RB. GSK1120212 also enhanced the G2/M phase arrest caused by radiation therapy and significantly decreased cell number in S phase. Ultimately, this led to cellular senescence selectively in KRAS mutant but not WT cells. At the dose chosen for this study (IC30), GSK1120212 didn't augment DNA damage or induce cell apoptosis caused by radiation. Taken together, our data suggested that MEK inhibitor GSK1120212 may have some selectivity in enhancing radiation effects in KRAS mutant lung cancer cells. A phase I clinical trial is currently ongoing to test the safety and preliminary efficacy of combining GSK1120212 and chemoradiation in locally advanced NSCLC. Citation Format: Steven H. Lin, Jing Zhang, Uma Giri, John V. Heymach. Enhancement of radiation response in KRAS mutant non-small cell lung cancer cells with the MEK inhibitor GSK1120212. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4442. doi:10.1158/1538-7445.AM2013-4442