Molecular Pathways: Targeting the CXCR4-CXCL12 Axis--Untapped Potential in the Tumor Microenvironment

Clin Cancer Res. 2015 Oct 1;21(19):4278-85. doi: 10.1158/1078-0432.CCR-14-0914. Epub 2015 Jul 21.

Abstract

Evidence suggests that the CXC-chemokine receptor-4 pathway plays a role in cancer cell homing and metastasis, and thus represents a potential target for cancer therapy. The homeostatic microenvironment chemokine CXCL12 binds the CXCR4 and CXCR7 receptors, activating divergent signals on multiple pathways, such as ERK1/2, p38, SAPK/JNK, AKT, mTOR, and the Bruton tyrosine kinase (BTK). An activating mutation in CXCR4 is responsible for a rare disease, WHIM syndrome (warts, hypogammaglobulinemia, infections, and myelokathexis), and dominant CXCR4 mutations have also been reported in Waldenstrom macroglobulinemia. The CXCR4-CXCL12 axis regulates the hematopoietic stem cell niche--a property that has led to the approval of the CXCR4 antagonist plerixafor (AMD3100) for mobilization of hematopoietic precursors. In preclinical models, plerixafor has shown antimetastatic potential in vivo, offering proof of concept. Other antagonists are in preclinical and clinical development. Recent evidence demonstrates that inhibiting CXCR4 signaling restores sensitivity to CTLA-4 and PD-1 checkpoint inhibitors, creating a new line for investigation. Targeting the CXCR4-CXCL12 axis thus offers the possibility of affecting CXCR4-expressing primary tumor cells, modulating the immune response, or synergizing with other targeted anticancer therapies.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Chemokine CXCL12 / metabolism*
  • Clinical Trials as Topic
  • Drug Discovery
  • Drug Evaluation, Preclinical
  • Humans
  • Molecular Targeted Therapy
  • Neoplasms / drug therapy
  • Neoplasms / genetics
  • Neoplasms / immunology
  • Neoplasms / metabolism*
  • Neoplasms / pathology*
  • Receptors, CXCR4 / antagonists & inhibitors
  • Receptors, CXCR4 / metabolism*
  • Signal Transduction / drug effects*
  • Translational Medical Research
  • Treatment Outcome
  • Tumor Microenvironment / drug effects*
  • Tumor Microenvironment / genetics
  • Tumor Microenvironment / immunology

Substances

  • Antineoplastic Agents
  • Chemokine CXCL12
  • Receptors, CXCR4