title: 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.affiliation: Authors' Affiliations: Candiolo Cancer Instiute-FPO (IRCCS), Center for Experimental Clinical Molecular Oncology and Department of Oncology, University of Torino, Candiolo, Torino, Italy carla.boccaccio@ircc.it antonella.cignetto@ircc.it.
authors.forename: Carla
authors.initials: C
authors.lastname: Boccaccio
authors.affiliation: Authors' Affiliations: Candiolo Cancer Instiute-FPO (IRCCS), Center for Experimental Clinical Molecular Oncology and.
authors.forename: Paolo
authors.initials: P
authors.lastname: Luraghi
authors.affiliation: Authors' Affiliations: Candiolo Cancer Instiute-FPO (IRCCS), Center for Experimental Clinical Molecular Oncology and Department of Oncology, University of Torino, Candiolo, Torino, Italy carla.boccaccio@ircc.it antonella.cignetto@ircc.it.
authors.forename: Paolo M
authors.initials: PM
authors.lastname: Comoglio
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met