Novel multi-kinase inhibitor shows early promise in NSCLC

By Joanna Lyford, Senior medwireNews Reporter

Researchers have reported promising early data on an investigational drug that targets two tyrosine kinase receptors that drive invasive growth and drug resistance in non-small-cell lung cancer (NSCLC).

The drug, known as NPS-1034, targets MET and AXL and was found to significantly inhibit tumor growth in human NSCLC cell lines and xenograft mouse models with acquired resistance to gefitinib or erlotinib.

Jae Cheol Lee (University of Ulsan, Seoul, Korea) and co-workers performed preclinical studies with NPS-1034, a synthetic drug that was primarily developed to inhibit MET but subsequently found to inhibit several other kinases, such as AXL, CSF1R, DDR, FLT3, KIT, MERTK, MST1R, ROS, TIE1, and TRK.

“Although NPS-1034 has inhibitory activity on various kinases, it may be most useful as a dual inhibitor of AXL and MET,” write Lee et al in Cancer Research.

They team first applied the drug to human NSCLC cell lines, finding that concurrent treatment with NPS-1034 and gefitinib overcame drug resistance caused by MET gene amplification. This resulted in inhibition of cell proliferation and induction of cell death.

The same effect was observed in immunocompromised mice, in which coadministration of NPS-1034 and gefitinib led to substantial inhibition of tumor growth.

Similarly, combined treatment of NSCLC cell lines with NPS-1034 and erlotinib overcame AXL-mediated drug resistance, via complete inhibition of epidermal growth factor receptor (EGFR) downstream signaling, leading to cell death.

NPS-1034 treatment of the mutant EGFR-expressing NSCLC cell line H820 caused these cells to become sensitive to treatment with an EGFR tyrosine kinase inhibitor (TKI).

Finally, the drug also inhibited ROS1 activity and was a potent inhibitor of cell proliferation in NSCLC cells harboring a ROS1 rearrangement. Indeed, the degree of inhibition was similar to that produced by crizotinib, suggesting a further possible clinical application of the drug.

The researchers conclude: “NPS-1034 is a very active agent in EGFR-mutant NSCLC with resistance to EGFR-TKIs via the bypass signals of MET or AXL and in ROS1-rearranged NSCLC.”

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