Met and HGF inhibition in triple-negative breast cancer cell lines.

Abstract

1066 Background: Basal-like breast cancer (BLBC) is associated with high expression of c-Met. c-Met and its ligand HGF may be rational therapeutic targets for BLBC. We evaluated expression of c-Met and response to c-Met/HGF inhibition alone/in combination with other targeted therapies in triple-negative breast cancer (TNBC) cell lines. Methods: Expression and phosphorylation of c-Met was measured by immunoblotting. qRT-PCR was used to measure HGF mRNA. Cell proliferation was measured by acid phosphatase assay after 5 day treatment with a c-Met inhibitor (CpdA), HGF monoclonal antibody, rilotumamab, a panHER inhibitor (neratinib) and a SRC kinase inhibitor, (saracatinib). Invasion through 0.4 μm Matrigel coated membranes was measured for two cell lines. Results: c-Met and p-Met were detected in 7 and 4 of the 7 TNBC cell lines tested, respectively. HGF mRNA was not detectable in any of the TN cell lines. CpdA inhibited growth in 4 TN cell lines with IC50values ranging from 2.1-7.6 μM. Rilotumumab did not inhibit growth, however combined treatment with CpdA and rilotumumab resulted in significantly increased growth inhibition in 3 of 5 cell lines (Table). CpdA in combination with neratinib significantly improved growth inhibition in MDA-MB-468 cells, and in combination with saracatinib significantly improved growth inhibition in 3 of 5 cell lines (Table). CpdA also inhibited invasion of CAL-85-1 cells by 21.4% (± 10.4%) but not HDQ-P1cells. Conclusions: c-Met may represent a viable molecular target in TNBC. Dual targeting of Met and HGF and/or with EGFR or SRC may increase the efficacy of c-Met inhibition in TNBC. [Table: see text]