Abstract 629: Hepatocyte growth factor induces resistance to an irreversible epidermal growth factor receptor inhibitor in EGFR-T790M mutant lung cancer

Abstract

Abstract Purpose: Epidermal growth factor receptor (EGFR)-activating mutations, such as deletion in exon 19 and L858R point mutation in exon 21,were found in non-small cell lung cancer and associated with favorable response to the reversible EGFR tyrosine kinase inhibitors (EGFR-TKI), gefitinib and erlotinib. However, almost all NSCLC patients with EGFR mutations who show response to reversible EGFR-TKI ultimately develop resistance to these agents. Recently, several mechanisms were reported to induce acquired resistance to reversible EGFR-TKI for non-small cell lung cancer with EGFR-activating mutations. Of these, the secondary T790M mutation in EGFR is the most frequent cause of acquired resistance to the reversible EGFR-TKI. Irreversible EGFR-TKIs are expected to overcome the reversible EGFR-TKI resistance of lung cancer harboring T790M mutation in EGFR. However, it is clear that resistance may also develop to this class of inhibitors. We showed previously that hepatocyte growth factor (HGF) induced gefitinib resistance of lung cancer harboring EGFR-activating mutations. Here, we investigated whether HGF induced resistance to the irreversible EGFR-TKI, CL-387,785, in lung cancer cells (H1975) harboring both L858R activating mutation and T790M secondary mutation in EGFR. Experimental Design: CL-387,785 sensitivity and signal transduction in H1975 cells were examined in the presence or absence of HGF or HGF-producing fibroblasts with or without HGF-MET inhibitors. Results: HGF induces resistance to CL-387,785 in H1975 cells. Western blotting and small interfering RNA analyses indicated that HGF-induced resistance was mediated by the MET/phosphoinositide 3-kinase/Akt signaling pathway independent of EGFR, ErbB2, ErbB3, and ErbB4. Resistance of H1975 cells to CL-387,785 was also induced by coculture with high-level HGF-producing lung fibroblasts. The resistance was abrogated by treatment with anti-HGF neutralizing antibody, HGF antagonist NK4, or MET-TKI. Conclusions: We showed HGF-mediated resistance as a novel mechanism of resistance to irreversible EGFR-TKIs. Our findings provide a novel insight into the involvement of HGF-MET mediated signaling in de novo and acquired resistance to irreversible EGFR-TKIs in lung cancer harboring T790M mutation in EGFR. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 629.