Abstract 4394: Identification of molecular determinants of response to GSK1120212B, a potent and selective MEK inhibitor, as a single agent and in combination in RAS/RAF mutant non-small cell lung carcinoma cells

Abstract

Abstract MEK, a downstream effector for RAS, RAF and receptor tyrosine kinases, represents a promising target for treatment of RAS/RAF mutated Non Small Cell Lung Carcinoma (NSCLC). GSK1120212B is a highly potent and selective oral MEK inhibitor currently in phase II clinical trials. To identify markers of response to GSK1120212B and to generate hypotheses for effective combination therapies, we characterized baseline signaling pathways and gene expression profiles in a panel of 29 NSCLC lines with RAS/RAF mutations and determined their sensitivity to GSK1120212B, erlotinib (EGFR inhibitor), everolimus (mTOR inhibitor), docetaxel and the combination of GSK1120212B with these agents. Inhibition of cell growth and induction of apoptosis were determined after 72 and 24 hours of treatment, respectively. GSK1120212B potently inhibited cell growth (IC50≤ 50 nM) in 13/29 (45%) of the lines and induced apoptosis in 8/29 (28%) of cell lines. We also identified genes such as TGFA, EREG, LGALS3, CTNND1, ARHGEF3, KLF4, RPH3AL, STN2, TWIST2 and FOXC1 whose expression levels were highly associated with the response to GSK1120212B. Cell signaling analyzed at baseline demonstrated that sensitivity to GSK1120212B was associated with high levels of pMEK, low levels of pAKT/pFOXO3a and wild-type PTEN, and resistance was associated with high levels of pAKT/pFOXO3a or mutations of PTEN/PIK3CA/CTNNB1 in RAS/RAF mutant lines. These results suggest combination approaches for cell lines resistant to single agent GSK1120212B. Erlotinib or everolimus alone showed little activity in RAS/RAF mutant lines. The combination of GSK1120212B and erlotinib was synergistic and/or enhanced cell growth inhibition in 6 out of 10 RAS/RAF mutant lines tested, three of which had HER1 amplification or over-express TGFA and EREG. The combination of GSK1120212B and everolimus enhanced cell growth inhibition in 25/29 (86%) of cell lines and increased apoptosis in 12/28 (43%) of RAS/RAF mutant lines. Intriguingly, the RAS/RAF mutated lines that were sensitive to GSK1120212B alone as measured by induction of apoptosis were less responsive to docetaxel. Further, the combination of GSK1120212B and docetaxel was synergistic or increased apoptosis in 20/28 RAS/RAF mutated lines. Our results provide a strong rationale for testing GSK1120212B and these combinations in the clinic and warrant further investigation of the gene expression signatures and genetic mutations in patients to ultimately improve treatment outcome in RAS/RAF mutated NSCLC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4394. doi:10.1158/1538-7445.AM2011-4394