Abstract B50: ERK MAPK inhibition enhances the immunogenicity of KRAS-mutant colorectal cancer

Abstract

Abstract The three RAS genes are the most commonly mutated oncogenes in cancer and are refractory to conventional therapies. Oncogenic mutation of KRAS in 44% of colorectal cancers (CRC) leads to aberrant activation of downstream effector pathways, including the ERK MAPK signaling cascade, which can lead to an immunosuppressive tumor microenvironment. Single-agent therapies targeting the ERK MAPK cascade or immune checkpoint (PD-1/PD-L1) have been mostly unsuccessful in KRAS-mutant CRC, and efforts are under way to identify effective combination strategies. We employed an unbiased RNA-seq approach to identify gene signatures significantly upregulated upon ERK MAPK pathway inhibition in a panel of KRAS-mutant CRC cell lines. We found that treatment with either the MEK inhibitor trametinib or ERK inhibitor Vx-11e induced upregulation of interferon gene signatures and JAK/STAT pathway signaling components. Inhibition of MEK or ERK also transcriptionally increased levels of MHC Class I and antigen presentation machinery. Upregulation of MHC Class I was reversed with either pharmacologic inhibition of JAK/STAT signaling or genetic knockdown of the transcription factor IRF1. We propose that combining MAPK inhibition with checkpoint immunotherapy may provide an effective treatment in KRAS-mutant CRC tumors in vivo and that potential synergy may be due to enhancing the immunogenicity of tumors through priming of interferon response pathways and antigen presentation machinery. Citation Format: Meagan B. Ryan, Ferran Fece de la Cruz, Leanne G. Ahronian, Sarah Phat, David T. Myers, Heather A. Shahzade, Catriona Hong, Ryan B. Corcoran. ERK MAPK inhibition enhances the immunogenicity of KRAS-mutant colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr B50.