Abstract 955: Specific forms of mutant KRAS predict patient benefit from targeted therapy in the BATTLE-1 clinical trial in advanced non-small cell lung cancer

Abstract

Abstract Mutant KRAS (mut-KRAS) is present in 17-25% of all human cancers, where it plays a critical role in driving cancer cell growth and resistance to therapy. Despite numerous attempts, there is still no effective therapy for mut-KRAS tumors. Understanding the signaling mechanisms activated by mut-KRAS and finding agents to inhibit mut-KRAS signaling are important unmet needs in cancer therapy today. The recently completed BATTLE-1 clinical trial, a prospective, multi-arm, biopsy-mandated, biomarker-driven, clinical trial in advanced refractory non-small cell lung cancer (NSCLC), found that mut-KRAS did not accurately predict patient outcome (progression-free survival) to targeted intervention. This finding contradicted published evidence for such a relationship from colon cancer and some previous NSCLC studies. We explored more specifically the nature of the KRAS mutations, which are primarily found at codons 12 and 13, where different base substitutions lead to alternate amino acid (aa) substitutions. NSCLC has a much higher proportion of mut-KRAS G12C(cysteine) aa substitutions (47%) due to carcinogens in tobacco smoke, and only 15% mut-KRAS have G12D(aspartate). These data contrast those in other solid tumors, such as colon or pancreas, which predominantly manifest mut-KRAS G12D (50%) and only 9% mut-KRAS G12C. In a subset analysis of the BATTLE-1 data, we showed significantly worse progression-free survival in patients with mut-KRAS G12C, versus other mut-KRAS including G12D (p=.041) and who were treated with erlotinib, vandetanib or sorafenib. In a panel of NSCLC cell lines with known mut-KRAS aa substitutions to identify pathways activated by the different mut-KRAS genotypes, we found that mut-KRAS G12D activates both PI-3-K and MEK signaling, while mut-KRAS G12C does not and alternatively activates PKCζ and RAL signaling. This finding was confirmed in immortalized human bronchial epithelial (HBEC) cells stably transfected with wt-KRAS or different forms of mut-KRAS. Our molecular modeling studies show that the different conformation imposed by mut-KRAS G12C could lead to altered association with downstream signaling transducers, compared to mut-KRAS G12D. The significance of the findings for developing mut-KRAS therapies is profound, since it suggests that not all mut-KRAS may be addictive; and that different combinations of inhibitors of downstream signaling may be needed for different mut-KRAS. 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 955. doi:10.1158/1538-7445.AM2011-955