nps-1034 and Lung-Neoplasms

A novel EGFR-tyrosine kinase inhibitor (TKI), osimertinib, has marked efficacy in patients with EGFR-mutated lung cancer. However, some patients show intrinsic resistance and an insufficient response to osimertinib. This study showed that osimertinib stimulated AXL by inhibiting a negative feedback loop. Activated AXL was associated with EGFR and HER3 in maintaining cell survival and inducing the emergence of cells tolerant to osimertinib. AXL inhibition reduced the viability of EGFR-mutated lung cancer cells overexpressing AXL that were exposed to osimertinib. The addition of an AXL inhibitor during either the initial or tolerant phases reduced tumor size and delayed tumor re-growth compared to osimertinib alone. AXL was highly expressed in clinical specimens of EGFR-mutated lung cancers and its high expression was associated with a low response rate to EGFR-TKI. These results indicated pivotal roles for AXL and its inhibition in the intrinsic resistance to osimertinib and the emergence of osimertinib-tolerant cells.

Topics: Acrylamides; Adenocarcinoma of Lung; Adult; Aniline Compounds; Animals; Antineoplastic Combined Chemotherapy Protocols; Axl Receptor Tyrosine Kinase; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Survival; Disease-Free Survival; Drug Resistance, Neoplasm; ErbB Receptors; Female; Gene Knockdown Techniques; Heterocyclic Compounds, 2-Ring; Humans; Lung; Lung Neoplasms; Male; Mice; Mice, Inbred NOD; Mutation; Neoplasm Recurrence, Local; Piperazines; Protein Kinase Inhibitors; Proto-Oncogene Proteins; Pyrazoles; Receptor Protein-Tyrosine Kinases; Receptor, ErbB-3; RNA, Small Interfering; Treatment Outcome; Xenograft Model Antitumor Assays

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.

Topics: Animals; Axl Receptor Tyrosine Kinase; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; ErbB Receptors; Female; Heterocyclic Compounds, 2-Ring; Humans; Lung Neoplasms; Mice; Mice, SCID; Protein Kinase Inhibitors; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-met; Pyrazoles; Receptor Protein-Tyrosine Kinases; RNA, Small Interfering; Transfection; Xenograft Model Antitumor Assays