Abstract 4184: Pre-clinical study using KRAS mutant mouse models for lung cancer immunotherapy together with MEK inhibition

Abstract

Abstract Activating KRAS mutations are identified as the most common driver oncogene for lung adenocarcinomas, accounts for 20∼30% of lung cancer patients. The development of therapeutic strategy for KRAS mutant lung cancer patients remains to be an unmet need, due to poor prognosis and therapeutic resistance to conventional therapy. The purpose of our study is through utilizing different types of genetically engineered mouse models (GEMMs), to understand the molecular heterogeneity of KRAS mutant lung cancer, to define the immune microenvironment, and to determine the feasibility and strategy of using MEK inhibition in combination with immune checkpoint inhibitors for the treatment of KRAS mutant lung cancer. We generated two different types of GEMMs with KRAS mutations that develop tumor in the lung: Kras with G12D mutation or KRAS with G12C mutation. Continuous treatment of either KrasG12D or KRASG12C mice with MEK inhibitor Selumetinib (AZD6244, ARRY-142886) shows short-term response followed by drug resistance to single regimen treatment. The immuno-profiling shows that Selumetinib can increase cytotoxic T cells percentage and decrease PD-L1 expression on both myeloid cells and lymphocytes. Prolonged treatment of Selumetinib on KRAS mutant mice will lead to down-regulation of the expression of immune-checkpoint inhibitory factors Ctla-4 and Pd-1 on both CD4+ and CD8+ T cells. When KRAS mutant mice are treated with Selumetinib intermittently, they show improved response comparing with continuous treatment. When combining MEK inhibition with immune checkpoint blockade by using Selumetinib together with Pd-1 antibody treatment, Tim3 and Ctla-4 expression on T cells is increased potentially leading to T cell exhaustion and immune suppression in lung cancer. These pre-clinical results provide molecular insight for the immune response to MEK inhibition in KRAS driven lung cancer. Furthermore, these data support our hypothesis that MEK inhibition combination with immune checkpoint blockade treatment will have better outcome for lung cancer patients that have KRAS mutation through activating T cell response. Citation Format: Jiehui Deng, Shuai Li, Grit Herter-Sprie, Paul D. Smith, Gordon J. Freeman, Jeffrey A. Engelman, Peter Hammerman, Kwok-Kin Wong. Pre-clinical study using KRAS mutant mouse models for lung cancer immunotherapy together with MEK inhibition. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4184.