J Cancer 2014; 5(9):745-753. doi:10.7150/jca.9696
cMET Activation and EGFR-Directed Therapy Resistance in Triple-Negative Breast Cancer
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
3. Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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.
Conclusion: 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.
Keywords: cMET, EGFR, Therapy resistance, Triple-negative breast cancer
Sohn J, Liu S, Parinyanitikul N, Lee J, Hortobagyi GN, Mills GB, Ueno NT, Gonzalez-Angulo AM. cMET Activation and EGFR-Directed Therapy Resistance in Triple-Negative Breast Cancer. J Cancer 2014; 5(9):745-753. doi:10.7150/jca.9696. Available from http://www.jcancer.org/v05p0745.htm