Drug resistance and new therapies in colorectal cancer

• Published in: World journal of gastroenterology : WJG Vol. 24; no. 34; pp. 3834 - 3848
• Main Authors: Jeught, Kevin Van der, Xu, Han-Chen, Li, Yu-Jing, Lu, Xiong-Bin, Ji, Guang
• Format: Journal Article
• Language: English
• Published: United States Baishideng Publishing Group Inc 14.09.2018
• Subjects: Alpha-Amanitin - pharmacology; Alpha-Amanitin - therapeutic use; Antineoplastic Agents, Immunological - pharmacology; Antineoplastic Agents, Immunological - therapeutic use; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - immunology; Colorectal Neoplasms - mortality; Costimulatory and Inhibitory T-Cell Receptors - antagonists & inhibitors; Costimulatory and Inhibitory T-Cell Receptors - immunology; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Drug Resistance, Neoplasm - immunology; Humans; Immunoconjugates - pharmacology; Immunoconjugates - therapeutic use; Immunotherapy - methods; Microsatellite Instability - drug effects; Nucleic Acid Synthesis Inhibitors - pharmacology; Nucleic Acid Synthesis Inhibitors - therapeutic use; Review; RNA Polymerase II - antagonists & inhibitors; Treatment Outcome; Tumor Escape - drug effects; Tumor Escape - genetics; Tumor Escape - immunology; Tumor Microenvironment - drug effects; Tumor Microenvironment - immunology; Tumor Suppressor Protein p53 - genetics; Checkpoint inhibitors; Therapy resistance; Tumor microenvironment; α-amanitin; Immunotherapy; Colorectal cancer; Antibody-drug conjugates; Microbiome
• DOI: 10.3748/wjg.v24.i34.3834
• ISSN: 1007-9327; 2219-2840

Colorectal cancer (CRC) is often diagnosed at an advanced stage when tumor cell dissemination has taken place. Chemo- and targeted therapies provide only a limited increase of overall survival for these patients. The major reason for clinical outcome finds its origin in therapy resistance. Escape mechanisms to both chemo- and targeted therapy remain the main culprits. Here, we evaluate major resistant mechanisms and elaborate on potential new therapies. Amongst promising therapies is α-amanitin antibody-drug conjugate targeting hemizygous p53 loss. It becomes clear that a dynamic interaction with the tumor microenvironment exists and that this dictates therapeutic outcome. In addition, CRC displays a limited response to checkpoint inhibitors, as only a minority of patients with microsatellite instable high tumors is susceptible. In this review, we highlight new developments with clinical potentials to augment responses to checkpoint inhibitors.