| Reference | 1. Invest New Drugs. 2014 Jun;32(3):389-99. doi: 10.1007/s10637-013-0039-4. Epub
2013 Oct 31.
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NPS-1034, a novel MET inhibitor, inhibits the activated MET receptor and its
constitutively active mutants.
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Shin JS(1), Hong SW, Moon JH, Kim JS, Jung KA, Kim SM, Lee DH, Kim I, Yoon SJ,
Lee CG, Choi EK, Lee JY, Kim KP, Hong YS, Lee JL, Kim B, Choi EK, Lee JS, Jin DH,
Kim TW.
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Author information: <br>
(1)Institute for Innovative Cancer Research, University of Ulsan College of
Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736,
Seoul, Republic of Korea.
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The MET proto-oncogene product, which is the receptor for hepatocyte growth
factor (HGF), has been implicated in tumorigenesis and metastatic progression.
Point mutations in MET lead to the aberrant activation of the receptor in many
types of human malignancies, and the deregulated activity of MET has been
correlated with tumor growth, invasion, and metastasis. MET has therefore
attracted considerable attention as a potential target in anticancer therapy.
Here, we report that a novel MET kinase inhibitor, NPS-1034, inhibits various
constitutively active mutant forms of MET as well as HGF-activated wild-type MET.
NPS-1034 inhibited the proliferation of cells expressing activated MET and
promoted the regression of tumors formed from such cells in a mouse xenograft
model through anti-angiogenic and pro-apoptotic actions. NPS-1034 also inhibited
HGF-stimulated activation of MET signaling in the presence or absence of serum.
Furthermore, when tested on 27 different MET variants, NPS-1034 inhibited 15 of
the 17 MET variants that exhibited autophosphorylation with nanomolar potency;
only the F1218I and M1149T variants were not inhibited by NPS-1034. Notably,
NPS-1034 inhibited three MET variants that are resistant to the MET inhibitors
SU11274, NVP-BVU972, and PHA665752. Together, these results suggest that NPS-1034
can be used as a potent therapeutic agent for human malignancies bearing MET
point mutations or expressing activated MET.
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2. Cancer Res. 2014 Jan 1;74(1):253-62. doi: 10.1158/0008-5472.CAN-13-1103. Epub
2013 Oct 28.
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MET and AXL inhibitor NPS-1034 exerts efficacy against lung cancer cells
resistant to EGFR kinase inhibitors because of MET or AXL activation.
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Rho JK(1), Choi YJ, Kim SY, Kim TW, Choi EK, Yoon SJ, Park BM, Park E, Bae JH,
Choi CM, Lee JC.
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Author information: <br>
(1)Authors/’ Affiliations: Department of Pulmonology and Critical Care Medicine;
Asan Institute for Life Sciences; Departments of Oncology and Radiation Oncology,
Asan Medical Center, College of Medicine, University of Ulsan, Songpa-gu, Seoul;
and Department of New Drug Discovery, Neopharm, Daejeon, South Korea.
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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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