Abstract 1692:KRAS-mediated therapeutic resistance abrogates immunogenic cell death in colorectal cancer cells

A hallmark of cancer is compromised immune surveillance, which is characterized by failure of the immune system to recognize tumor-associated antigens and specifically eliminate malignant cells. A number of studies showed the tumor microenvironment in colorectal cancer (CRC) patients is highly immunosuppressive. Conventional chemotherapy and recent targeted therapy can restore anti-tumor immune response through induction of immunogenic cell death (ICD) in tumor cells. However, the mechanism and functional role of ICD in CRC treatment remains vague. In this study, we found FOLFIRI (Leucovorin/5-Fluorouracil/Irinotecan) combined with the anti-EGFR antibody cetuximab, a commonly used regimen for CRC treatment, induces death of CRC cells with characteristics of necroptosis, including ATP depletion, release of HMGB1, and phosphorylation of RIP3 and MLKL. Cells subjected to the combination treatment exhibited features of ICD including plasma membrane exposure of calreticulin and phagocytosis by dendritic cells. We identified the BH3-only Bcl-2 family protein PUMA as a key mediator of necroptosis induced by the combination treatment in vitro and in vivo. Furthermore, we found that CRC cells with acquired cetuximab resistance due to KRAS mutation or amplification are deficient in ICD. Collectively, our results suggest that oncogenic mutations cause resistance of CRC cells to anticancer therapies in part by suppressing ICD. Citation Format: Yi-Jun Wang, Dongshi Chen, Jingshan Tong, Jian Yu, Alberto Bardelli, Lin Zhang. KRAS-mediated therapeutic resistance abrogates immunogenic cell death in colorectal cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1692. doi:10.1158/1538-7445.AM2017-1692