Targeting MET and EGFR crosstalk signaling in triple-negative breast cancers

Erik S. Linklater, Elizabeth A. Tovar, Curt J. Essenburg, Lisa Turner, Zachary Madaj, Mary E. Winn, Marianne K. Melnik, Hasan Korkaya, Christiane R. Maroun, James G. Christensen, Matthew R. Steensma, Julie L. Boerner, Carrie R. Graveel

Research output: Contribution to journalArticle

20 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)69903-69915
Number of pages13
JournalOncotarget
Volume7
Issue number43
DOIs
Publication statusPublished - Jan 1 2016

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Keywords

  • EGFR
  • MET
  • Receptor tyrosine kinase
  • Triple-negative breast cancer
  • Tyrosine kinase inhibitors

ASJC Scopus subject areas

  • Oncology

Cite this

Linklater, E. S., Tovar, E. A., Essenburg, C. J., Turner, L., Madaj, Z., Winn, M. E., ... Graveel, C. R. (2016). Targeting MET and EGFR crosstalk signaling in triple-negative breast cancers. Oncotarget, 7(43), 69903-69915. https://doi.org/10.18632/oncotarget.12065