Abstract KRAS activating mutations are detected in 30% Non-Small Cell Lung Cancer (NSCLC) cases, and represent the subset of patients with the worst prognosis. Current efforts to develop treatments for this type of lung cancer are partially focused on inhibiting the Raf/MEK/ERK signaling cascade downstream of KRAS. Inhibition of the Raf/MEK/ERK pathway results in death of many mutant KRAS-driven lung cancer cell lines in vitro, and we have previously reported a murine active Kras lung cancer model that showed significant tumor regression upon treatment with the MEK inhibitor, selumetinib, when it was combined with other agents, such as PI3K/mTOR dual inhibitor BEZ235 or the cytotoxic agent docetaxel. The activity of the latter combination was validated in a recent phase II clinical trial in NSCLC patients harboring KRAS mutations. However, the responses were not durable in either human patients or mice, as resistance develop rapidly following chronic MEK inhibition. We have developed two approaches to reduce or delay the emergence of resistant clones. First, we have identified a number of novel treatment strategies that would directly improve the initial efficacy of MEK/ERK inhibition to dramatically enhance the initial response to MEK inhibition. Second, we have designed chemical screening strategies that identify compounds that act against active Kras lung cancer independently from the Raf/MEK/ERK pathway. We are using the first approach to delay the development of chronic resistance, while using the second approach to overcome resistance to MEK/ERK inhibition. Citation Format: Zhao Chen, Ellen Weisberg, Katherine Cheng, Andrew L. Kung, James Bradner, James Griffin, Kwok-Kin Wong. Improve MEK/ERK targeting in mutant KRAS lung cancer. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr B01. doi: 10.1158/1557-3125.RASONC14-B01