Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA.
Cancer Cell. 2010 Jan 19;17(1):77-88. doi: 10.1016/j.ccr.2009.11.022.
MET amplification activates ERBB3/PI3K/AKT signaling in EGFR mutant lung cancers and causes resistance to EGFR kinase inhibitors. We demonstrate that MET activation by its ligand, HGF, also induces drug resistance, but through GAB1 signaling. Using high-throughput FISH analyses in both cell lines and in patients with lung cancer, we identify subpopulations of cells with MET amplification prior to drug exposure. Surprisingly, HGF accelerates the development of MET amplification both in vitro and in vivo. EGFR kinase inhibitor resistance, due to either MET amplification or autocrine HGF production, was cured in vivo by combined EGFR and MET inhibition. These findings highlight the potential to prospectively identify treatment naive, patients with EGFR-mutant lung cancer who will benefit from initial combination therapy.
MET 扩增激活 EGFR 突变型肺癌中的 ERBB3/PI3K/AKT 信号通路，并导致对 EGFR 激酶抑制剂的耐药性。我们证明，其配体 HGF 对 MET 的激活也会通过 GAB1 信号诱导耐药性。通过在细胞系和肺癌患者中进行高通量 FISH 分析，我们在药物暴露之前鉴定出具有 MET 扩增的细胞亚群。令人惊讶的是，HGF 无论是在体外还是体内都能加速 MET 扩增的发展。由于 MET 扩增或自分泌 HGF 的产生导致的 EGFR 激酶抑制剂耐药性，通过联合 EGFR 和 MET 抑制在体内得到治愈。这些发现强调了有潜力前瞻性地识别治疗初治、受益于初始联合治疗的 EGFR 突变型肺癌患者的可能性。
