title: cMET Activation and EGFR-Directed Therapy Resistance in Triple-Negative Breast Cancer.
abstract: BACKGROUND
  EGFR expression and pathway activation are common in triple-negative breast cancer (TNBC). However, anti-EGFR therapies have not been effective in these patients. We aimed to study the efficacy of targeting MET in overcoming resistance to EGFR therapy in TNBC cell lines.
  
  
  METHODS
  TNBC lines (MDA-MB-468, HCC-1395, and MDA-MB-231), and a hormone receptor-positive breast cancer line (T47D) were stimulated with epidermal growth factor (EGF) and hepatocyte growth factor (HGF). Lines were then treated with different concentrations of EGFR inhibitors (gefitinib or cetuximab), with or without a MET tyrosine kinase inhibitor (EMD 1214063). Proliferation was measured by MTS assay, in soft agar and with a matrigel assay. Synergy was measured with Calcusyn. Protein expression and signaling were examined with immunoblotting.
  
  
  RESULTS
  There was activation of ligand-receptor-downstream signaling pathways in MDA-MB-468 and HCC-1395 upon stimulation with EGF and HGF. In these cell lines, we observed synergism when combining EGFR and MET inhibitors. These results were observed across assays. In western blotting, combination therapy resulted in abrogation of pAKT and pMAPK while monotherapy did not.
  
  
  CONCLUSIONS
  Our data demonstrate that dual EGFR/MET inhibition is synergistic in TNBC. Targeting both EGFR and MET receptors may provide an effective therapeutic strategy in TNBC.
authors.affiliation: 1. Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA ; 2. Division of Medical Oncology, Department of Internal Medicine, Breast Cancer Clinic, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Joohyuk
authors.initials: J
authors.lastname: Sohn
authors.affiliation: 1. Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Shuying
authors.initials: S
authors.lastname: Liu
authors.affiliation: 1. Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Napa
authors.initials: N
authors.lastname: Parinyanitikul
authors.affiliation: 1. Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jangsoon
authors.initials: J
authors.lastname: Lee
authors.affiliation: 1. Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Gabriel N
authors.initials: GN
authors.lastname: Hortobagyi
authors.affiliation: 3. Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: 1. Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Naoto T
authors.initials: NT
authors.lastname: Ueno
authors.affiliation: 1. Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA ; 3. Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Gonzalez-Angulo
keywords: EGFR; Therapy resistance; Triple-negative breast cancer; cMET