title: Targeting MET and EGFR crosstalk signaling in triple-negative breast cancers.
abstract: There is a vital need for improved therapeutic strategies that are effective in both primary and metastatic triple-negative breast cancer (TNBC). Current treatment options for TNBC patients are restricted to chemotherapy; however tyrosine kinases are promising druggable targets due to their high expression in multiple TNBC subtypes. Since coexpression of receptor tyrosine kinases (RTKs) can promote signaling crosstalk and cell survival in the presence of kinase inhibitors, it is likely that multiple RTKs will need to be inhibited to enhance therapeutic benefit and prevent resistance. The MET and EGFR receptors are actionable targets due to their high expression in TNBC; however crosstalk between MET and EGFR has been implicated in therapeutic resistance to single agent use of MET or EGFR inhibitors in several cancer types. Therefore it is likely that dual inhibition of MET and EGFR is required to prevent crosstalk signaling and acquired resistance. In this study, we evaluated the heterogeneity of MET and EGFR expression and activation in primary and metastatic TNBC tumorgrafts and determined the efficacy of MET (MGCD265 or crizotinib) and/or EGFR (erlotinib) inhibition against TNBC progression. Here we demonstrate that combined MET and EGFR inhibition with either MGCD265 and erlotinib treatment or crizotinib and erlotinib treatment were highly effective at abrogating tumor growth and significantly decreased the variability in treatment response compared to monotherapy. These results advance our understanding of the RTK signaling architecture in TNBC and demonstrate that combined MET and EGFR inhibition may be a promising therapeutic strategy for TNBC patients.
authors.affiliation: Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, Michigan, USA.
authors.forename: Erik S
authors.initials: ES
authors.lastname: Linklater
authors.affiliation: Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, Michigan, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Tovar
authors.affiliation: Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, Michigan, USA.
authors.forename: Curt J
authors.initials: CJ
authors.lastname: Essenburg
authors.affiliation: Pathology and Biorepository Core, Van Andel Research Institute, Grand Rapids, Michigan, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Turner
authors.affiliation: Bioinformatics and Biostatistics Core, Van Andel Research Institute, Grand Rapids, Michigan, USA.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Madaj
authors.affiliation: Bioinformatics and Biostatistics Core, Van Andel Research Institute, Grand Rapids, Michigan, USA.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Winn
authors.affiliation: Spectrum Health Cancer Center, Spectrum Health System, Grand Rapids, Michigan, USA.|Grand Rapids Medical Education Partners, General Surgery Residency Program, Grand Rapids, Michigan, USA.|Department of Surgery, Michigan State University College of Human Medicine, Grand Rapids, Michigan, USA.
authors.forename: Marianne K
authors.initials: MK
authors.lastname: Melnik
authors.affiliation: Molecular Oncology and Biomarkers Program, Augusta University, Augusta, Georgia, USA.
authors.forename: Hasan
authors.initials: H
authors.lastname: Korkaya
authors.affiliation: Mirati Therapeutics, San Diego, California, USA.|Current address: Vertex Pharmaceuticals (Canada) Inc., Laval, Quebec, Canada.
authors.forename: Christiane R
authors.initials: CR
authors.lastname: Maroun
authors.affiliation: Mirati Therapeutics, San Diego, California, USA.
authors.forename: James G
authors.initials: JG
authors.lastname: Christensen
authors.affiliation: Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, Michigan, USA.|Spectrum Health Cancer Center, Spectrum Health System, Grand Rapids, Michigan, USA.|Department of Surgery, Michigan State University College of Human Medicine, Grand Rapids, Michigan, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Steensma
authors.affiliation: Biobanking and Correlative Sciences Core, Karmanos Cancer Institute, Detroit, Michigan, USA.
authors.forename: Julie L
authors.initials: JL
authors.lastname: Boerner
authors.affiliation: Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, Michigan, USA.
authors.forename: Carrie R
authors.initials: CR
authors.lastname: Graveel
mesh_terms: D066246:ErbB Receptors / Q000032:analysis / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage; D005260:Female; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D019859:Proto-Oncogene Proteins c-met / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000235:genetics; D020239:Receptor Cross-Talk / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*; D064726:Triple Negative Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy*
chemical_list: D047428:Protein Kinase Inhibitors; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D019859:Proto-Oncogene Proteins c-met
keywords: EGFR; MET; receptor tyrosine kinase; triple-negative breast cancer; tyrosine kinase inhibitors