Met and c-Src Cooperate to Compensate for Loss of Epidermal Growth Factor Receptor Kinase Activity in Breast Cancer Cells

Abstract

Breast cancers are not responsive to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI), although 30% of breast cancers overexpress EGFR. The mechanism of intrinsic resistance to EGFR TKIs in breast cancer is the focus of current studies. Here, we observed that EGFR remains tyrosine phosphorylated in breast cancer cells that proliferate in the presence of EGFR TKIs. In one such cell line, SUM229, inhibiting c-Src kinase activity with either a dominantnegative c-Src or a c-Src TKI decreased EGFR phosphorylation on Tyr 845 , Tyr 992 , and Tyr 1086 in the presence of EGFR TKIs. Conversely, overexpressing wild-type (wt) c-Src in the EGFR TKI-sensitive breast cancer cell line SUM149 increased EGFR kinase-independent EGFR tyrosine phosphorylation. In addition, in the presence of EGFR TKIs, inhibiting c-Src kinase activity decreased cell growth in SUM229 cells, and overexpressing wt-c-Src increased cell growth in SUM149 cells. We identified the receptor tyrosine kinase Met to be responsible for activating c-Src in SUM229 cells. Inhibiting Met kinase activity with a small molecule inhibitor decreased c-Src phosphorylation and kinase activation. In addition, inhibiting Met kinase activity in SUM229 cells decreased EGFR tyrosine phosphorylation and growth in the presence of EGFR TKIs. Stimulating Met kinase activity in SUM149 cells with hepatocyte growth factor increased EGFR tyrosine phosphorylation and cell growth in the presence of EGFR TKIs. These data suggest a Met/c-Src-mediated signaling pathway as a mediator of EGFR tyrosine phosphorylation and cell growth in the presence of EGFR TKIs. [Cancer Res 2008;68(9):3314-22]

Association of constitutively activated hepatocyte growth factor receptor (Met) with resistance to a dual EGFR/Her2 inhibitor in non-small-cell lung cancer cells

“…ErbBs are implicated in promoting proliferation and survival, and Met has important roles in cell motility and epithelial/mesenchymal transition. Our identification of ErbB and Met signalling in a single lung cancer cell line, and the involvement in responsiveness to ErbB and Met inhibitors is consistent with other recent studies that highlighted functional cooperation between these two receptor families (Bean et al, 2007;Guo et al, 2008;Mueller et al, 2008;Shattuck et al, 2008;Yano et al, 2008). Interaction of these receptor families has been suggested for years, based on the finding that Met is often co-overexpressed with ErbBs in prostate and breast carcinoma.…”

Role of ErbB family receptor tyrosine kinases in intrahepatic cholangiocarcinoma

“…EGFR and/or ErbB2, Met, PDGFR, IL-6R) in solid malignant tumors results in redundant inputs that drive downstream signaling, therefore limiting the effectiveness of therapies that target just a single receptor tyrosine kinase [207] . For example, Met/c-Src signaling has been recently shown to mediate EGFR tyrosine phosphorylation and cell growth in cultured SUM229 breast cancer cells in the presence of EGFR-TKIs [208] . Presently, there is no uniform set of biomarkers that can be used to accurately predict a therapeutic response in solid tumors, including intrahepatic cholangiocarcinoma, to ErbB-directed therapies.…”

Antitumor Activity of Saracatinib (AZD0530), a c-Src/Abl Kinase Inhibitor, Alone or in Combination with Chemotherapeutic Agents in Gastric Cancer

“…Src is involved in the crosstalk between many signaling pathways, including the integrin/FAK, EGF receptor (EGFR), Ras/Raf/MEK, PI3K/AKT, and JAK/STAT pathways, which promote cell proliferation, adhesion, invasion, migration, metastasis, and tumorigenesis (1,2). A previous analysis found that 20% of human breast cancers overexpress both Src and EGFR, suggesting the involvement of Src in the EGFR signaling pathway (3). Another study found that Src activation is required for EGF-induced integrin-mediated migration and metastasis.…”