Abstract C141: KRAS G12C mutation is prognostic of poor outcome in resected lung adenocarcinomas and predictive of poor response to MEK inhibition in vitro.

Purpose: KRAS mutant tumors form 30% of all lung adenocarcinomas (AC). It is unknown whether specific amino acid substitutions of the KRAS gene give rise to differing outcomes following surgery for early-stage lung cancer. Furthermore, it is unknown whether these specific substitutions confer differential sensitivity to MEK inhibition. The aims of this study were to examine the effects of various KRAS mutant subtypes on outcome following surgery for early-stage lung AC and to assess the impact of KRAS mutant subtypes to MEK inhibition. Experimental Design: Using available clinical and sequencing data, we identified 181 patients (pts) with surgically resected lung AC for whom sequencing data for KRAS mutation status was available. A multivariate Cox PH model was used to identify factors associated with disease-free (DFS) and overall survival (OS). We tested various KRAS mutant lung AC cell lines for sensitivity to MEK inhibition. Gene-expression data from lung AC cell lines was analyzed in order to identify differentially expressed genes in KRAS G12C mutant cells compared to other type of KRAS mutations. Results: KRAS mutations were identified in 89 (49%) pts of which 58 (65%) were transversion mutations and 18 (20%) were transition mutations whereas in 13 (15%) cases the mutation position was not specified. Patients with KRAS mutation had a statistically significant shorter DFS (median, 28.5 months) compared with pts with KRAS wild-type (median not reached; Log-rank P = 0.009). Strikingly, pts with KRAS G12C mutant tumors had significantly shorter DFS (median, 16.8 months) compared to pts with KRAS mutant non-G12C and KRAS wild-type tumors (median, 49.8 months and not reached respectively; Log-rank P < 0.001). Interestingly, patients with KRAS G12D, G12A or G12V showed similar prognosis to KRAS wild-type. In addition, pts harboring KRAS G12C mutations had a significantly shorter OS (median, 28.2 months) compared to KRAS non-G12C or wild-type (median not reached for both, Log-rank P = 0.001). In the multivariate Cox model, KRAS G12C remained as an independent prognostic marker for DFS (HR = 2.55, 95% CI 1.56 - 4.16, P < 0.001) and for OS (HR = 2.29, 95% CI 1.32 - 4.01, P = 0.003). When treated with the MEK inhibitor, trametinib, KRAS G12C lung cancer cell lines exhibited a higher IC50 than G12D and wild-type KRAS lung cancer cell lines. Interestingly, NOTCH2 and NFKB1 were significantly overexpressed in KRAS G12C cells compared to non-G12C cells. A higher expression of NOTCH2 and HES1 in KRAS mutant G12C cells was confirmed by RT-PCR. These results suggest that a subset of KRAS mutant G12C tumors express stem cell markers, and we hypothesize that a strategy for treating these tumors may consist of combining gamma-secretase inhibitors with other drugs targeting downstream effectors of KRAS. Conclusions: In pts with early-stage resected lung AC, specific KRAS amino acid substitutions differentially affect outcome. Patients with KRAS G12C mutant lung AC had worse outcome compared to pts with KRAS non-G12C and KRAS wild-type. G12C mutant cell lines were more resistant to MEK inhibition. Microarray analysis of G12C mutant lung AC cell lines revealed overexpression of genes involved in stem cell properties and inflammation. Future studies of MEK inhibition should take into consideration the various subtypes of KRAS mutant tumors. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C141. Citation Format: Ernest Nadal, Hiroe Shiratsuchi, Guoan Chen, Christine Sam, Gregory P. Kalemkerian, David G. Beer, Nithya Ramnath. KRAS G12C mutation is prognostic of poor outcome in resected lung adenocarcinomas and predictive of poor response to MEK inhibition in vitro. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C141.