Reference Detail

Ref Type

Journal Article

PMID

(24165158)

Authors

Rho JK, Choi YJ, Kim SY, Kim TW, Choi EK, Yoon SJ, Park BM, Park E, Bae JH, Choi CM, Lee JC

Title

MET and AXL inhibitor NPS-1034 exerts efficacy against lung cancer cells resistant to EGFR kinase inhibitors because of MET or AXL activation.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer research	74	1	2014 Jan 01	253-62	Cancer Res

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
NPS-1034			AXL Inhibitor 30 MET Inhibitor 59	NPS-1034 inhibits AXL and MET, including mutant forms of MET, as well as other kinases, which potentially results in decreased tumor cell growth and may overcome MET or AXL mediated drug resistance (PMID: 24173966, PMID: 24165158).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
ROS1 rearrange	lung non-small cell carcinoma	sensitive	NPS-1034	Preclinical - Cell culture	Actionable	In a preclinical study, NPS-1034 inhibited ROS1 activity and proliferation of a non-small cell lung cancer cell line harboring a ROS1 rearrangement in culture (PMID: 24165158).	24165158