Targeting MET and EGFR crosstalk signaling in triple-negative breast cancers
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Erik S. Linklater1,*, Elizabeth A. Tovar1,*, Curt J. Essenburg1, Lisa Turner2, Zachary Madaj3, Mary E. Winn3, Marianne K. Melnik4,5,6, Hasan Korkaya7, Christiane R. Maroun8,10, James G. Christensen8, Matthew R. Steensma1,4,6, Julie L. Boerner9, Carrie R. Graveel1
1Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, Michigan, USA
2Pathology and Biorepository Core, Van Andel Research Institute, Grand Rapids, Michigan, USA
3Bioinformatics and Biostatistics Core, Van Andel Research Institute, Grand Rapids, Michigan, USA
4Spectrum Health Cancer Center, Spectrum Health System, Grand Rapids, Michigan, USA
5Grand Rapids Medical Education Partners, General Surgery Residency Program, Grand Rapids, Michigan, USA
6Department of Surgery, Michigan State University College of Human Medicine, Grand Rapids, Michigan, USA
7Molecular Oncology and Biomarkers Program, Augusta University, Augusta, Georgia, USA
8Mirati Therapeutics, San Diego, California, USA
9Biobanking and Correlative Sciences Core, Karmanos Cancer Institute, Detroit, Michigan, USA
10Current address: Vertex Pharmaceuticals (Canada) Inc., Laval, Quebec, Canada
*These authors contributed equally to this work
Carrie R. Graveel, email: email@example.com
Keywords: triple-negative breast cancer, receptor tyrosine kinase, MET, EGFR, tyrosine kinase inhibitors
Received: May 11, 2016 Accepted: September 01, 2016 Published: September 16, 2016
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.
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