MET and AXL Inhibitor NPS-1034 Exerts Efficacy against Lung Cancer Cells Resistant to EGFR Kinase Inhibitors Because of MET or AXL Activation

Abstract

In non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations, acquired resistance to EGFR-tyrosine kinase inhibitors (EGFR-TKI) can occur through a generation of bypass signals such as MET or AXL activation. In this study, we investigated the antitumor activity of NPS-1034, a newly developed drug that targets both MET and AXL, in NSCLC cells with acquired resistance to gefitinib or erlotinib (HCC827/GR and HCC827/ER, respectively). Characterization of H820 cells and evaluation of NPS-1034 efficacy in these cells were also performed. The resistance of HCC827/GR was mediated by MET activation, whereas AXL activation led to resistance in HCC827/ER. The combination of gefitinib or erlotinib with NPS-1034 synergistically inhibited cell proliferation and induced cell death in both resistant cell lines. Accordingly, suppression of Akt was noted only in the presence of treatment with both drugs. NPS-1034 was also effective in xenograft mouse models of HCC827/GR. Although the H820 cell line was reported previously to have T790M and MET amplification, we discovered that AXL was also activated in this cell line. There were no antitumor effects of siRNA or inhibitors specific for EGFR or MET, whereas combined treatment with AXL siRNA or NPS-1034 and EGFR-TKIs controlled H820 cells, suggesting that AXL is the main signal responsible for resistance. In addition, NPS-1034 inhibited cell proliferation as well as ROS1 activity in HCC78 cells with ROS1 rearrangement. Our results establish the efficacy of NPS-1034 in NSCLC cells rendered resistant to EGFR-TKIs because of MET or AXL activation or ROS1 rearrangement. Cancer Res; 74(1); 253-62. Ó2013 AACR.

Curcumin-induced downregulation of Axl receptor tyrosine kinase inhibits cell proliferation and circumvents chemoresistance in non-small lung cancer cells

“…The growing body of evidence also indicates that overexpression and/or activation of Axl is a novel mechanism to induce the acquired resistance to various anticancer drugs including cytotoxic agents and various tyrosine kinase inhibitors, especially EGF receptor inhibitors (gefitinib or erlotinib) (43,44). Consistently, our data also showed that the viabilities of cisplatin/taxol-resistant cells (A549/CisR, H460/CisR, A549/TR and H460/TR) were decreased by curcumin treatment (Figs.…”

Four-in-One Antibodies Have Superior Cancer Inhibitory Activity against EGFR, HER2, HER3, and VEGF through Disruption of HER/MET Crosstalk

“…Moreover, receptor crosstalk of MET plays a critical role in the development of resistance to EGFR family inhibitors. Amplification of MET occurs in patients with NSCLC who develop resistance to the RTK inhibitors such as gefitinib or erlotinib (11,43,44). In NSCLC cells selected for resistance to gefitinib or erlotinib in vitro, MET is amplified and activated and stimulates MET/EGFR or HER3 phosphorylation and signaling to AKT (11,25).…”

Axl Kinase as a Key Target for Oncology: Focus on Small Molecule Inhibitors

“…However, some FDA-approved or clinical molecules, developed to inhibit other kinases, were evaluated against Axl given its interest. Some potent Axl kinase inhibitors in development are described in the literature (45,46). However, as few data are available regarding their selectivity and their application as treatment, we do not describe them here.…”