@article{3056560,
    title = "The role of autophagy in the treatment of BRAF mutant colorectal carcinomas differs based on microsatellite instability status",
    author = "Koustas, E. and Papavassiliou, A.G. and Karamouzis, M.V.",
    journal = "PLOS ONE",
    year = "2018",
    volume = "13",
    number = "11",
    publisher = "Public Library of Science",
    doi = "10.1371/journal.pone.0207227",
    keywords = "B Raf kinase;  cetuximab;  ipilimumab;  mitogen activated protein kinase;  n (2,3 dihydroxypropoxy) 3,4 difluoro 2 (2 fluoro 4 iodoanilino)benzamide;  nivolumab;  panitumumab;  pembrolizumab;  B Raf kinase;  BRAF protein, human;  CD274 protein, human;  EGFR protein, human;  epidermal growth factor receptor;  immunological antineoplastic agent;  monoclonal antibody;  programmed death 1 ligand 1;  protein kinase inhibitor, apoptosis;  Article;  autophagy;  BRAF gene;  cell death;  cell viability;  colorectal carcinoma;  colorectal carcinoma cell line;  controlled study;  drug effect;  drug efficacy;  drug mechanism;  drug response;  enzyme inhibition;  gene targeting;  genetic association;  human;  human cell;  microsatellite instability;  phenotype;  tumor microenvironment;  antagonists and inhibitors;  autophagy;  Caco-2 cell line;  cell cycle checkpoint;  colorectal tumor;  genetics;  HCT 116 cell line;  immunotherapy;  mutation;  pathology;  tumor cell line, Antibodies, Monoclonal;  Antineoplastic Agents, Immunological;  Apoptosis;  Autophagy;  B7-H1 Antigen;  Caco-2 Cells;  Cell Cycle Checkpoints;  Cell Line, Tumor;  Colorectal Neoplasms;  ErbB Receptors;  HCT116 Cells;  Humans;  Immunotherapy;  Microsatellite Instability;  Mutation;  Protein Kinase Inhibitors;  Proto-Oncogene Proteins B-raf",
    abstract = "Autophagy has been identified as a catabolic mechanism in cells but its' role in cancer remains controversial. Autophagy has been characterized either as tumor suppressor or inducer mechanism in many tumor types. Monoclonal antibodies against EGFR (cetuximab and panitumumab) represent a major step in the treatment of mCRC. Several studies propose that cetuximab and panitumumab trigger autophagy which reveals a potential resistance mechanism to these agents. The last years immunotherapy appears to be a novel promising strategy for the treatment of patients with solid tumors, including colorectal cancer. Checkpoint inhibitors, such as anti-PD1 (nivolumab and pembrolizumab) and anti-CTLA-4 (ipilimumab) antibodies have already been developed and applied in mCRC patients with MSI-H phenotype. The association between mtBRAF and autophagy or MSI status has already been characterized. In our study, we identify the autophagy initiation through anti-EGFR monoclonal antibodies and checkpoint inhibitors in colorectal carcinoma cell lines according to microsatellite status. The combination of autophagy inhibition, anti-EGFR antibodies and checkpoint inhibitors as well as autophagy targeting, MEK inhibition and anti-EGFR antibodies or checkpoint inhibitors appears to be the best treatment approach for microsatellite instability high and stable colorectal cancer cell lines, respectively. Both combinatorial approaches reduce cell viability through the induction of apoptotic cell death. The findings of this study point out the importance of different approach for the treatment of BRAF mutant metastatic colorectal cancers based on their microsatelite instability phenotype. © 2018 Koustas et al.This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, orotherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication."
}