Drug resistance and new therapies in colorectal cancer

World J Gastroenterol. 2018 Sep 14;24(34):3834-3848. doi: 10.3748/wjg.v24.i34.3834.

Abstract

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.

Keywords: Antibody-drug conjugates; Checkpoint inhibitors; Colorectal cancer; Immunotherapy; Microbiome; Therapy resistance; Tumor microenvironment; α-amanitin.

Publication types

  • Review

MeSH terms

  • 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
  • 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

Substances

  • Alpha-Amanitin
  • Antineoplastic Agents, Immunological
  • Costimulatory and Inhibitory T-Cell Receptors
  • Immunoconjugates
  • Nucleic Acid Synthesis Inhibitors
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • RNA Polymerase II