MET-mediated resistance to EGFR inhibitors: an old liaison rooted in colorectal cancer stem cells.

Abstract

Inhibitors of EGFR are currently approved for the therapy of metastatic colorectal cancer (as well as other tumors), but their benefits are limited by inherent and acquired resistance, whose mechanisms are the subject of intense investigation. It is known that such resistance relies on a handful of genetic lesions and/or extracellular signals bypassing the requirement of EGF for cell proliferation and survival. As recently shown, these mechanisms may imply oncogenic activation of MET or its stimulation by the ligand hepatocyte growth factor. However, it is still largely obscure if sensitivity or resistance to EGFR inhibitors operates in cancer stem cells. Convincing evidence indicates that this elusive cell subpopulation is present at the roots of colorectal cancer. Conceivably, cancer stem cells accumulate the genetic lesions driving tumor onset and progression, as well as the genetic determinants of sensitivity or resistance to conventional and targeted therapies. Recent studies enlighten the expression of functional EGFR and MET in colorectal cancer stem cells and the outcome of their inhibition. Evidence is provided that, in patients sensitive to EGFR therapy, association of MET inhibitors fosters cancer stem cell eradication and durable tumor regression.

• Authors: Carla Boccaccio, Paolo Luraghi, Paolo M Comoglio
• Journal: Cancer research (Cancer Res) Vol. 74 Issue 14 Pg. 3647-51 (Jul 15 2014) ISSN: 1538-7445 [Electronic] United States
• PMID: 24986519 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• ErbB Receptors
• Proto-Oncogene Proteins c-met

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Colorectal Neoplasms (drug therapy, genetics, metabolism)
• Drug Resistance, Neoplasm (genetics)
• ErbB Receptors (antagonists & inhibitors)
• Humans
• Neoplastic Stem Cells (drug effects, metabolism)
• Proto-Oncogene Proteins c-met (genetics, metabolism)