Author of

• 18272

  +

  P3.01 - Poster Session with Presenters Present (ID 469)

  • Event: WCLC 2016
  • Type: Poster Presenters Present
  • Track: Biology/Pathology
  • Presentations: 1
  • Moderators:
  • Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)

  • 18326

    +

    P3.01-054 - Antagonism of a Novel Kinase, MAP3K19, By Specific Small Molecule Inhibitors Blocks Human Primary NSCLC Tumor Growth in Murine Xenograft Models (ID 6775)

    14:30 - 14:30  |  Author(s): J. Ludka
    • Abstract

    Background:
    We have identified a novel serine/threonine protein kinase, MAP3K19, whose expression in normal lung was predominantly localized to alveolar and interstitial macrophages, bronchial epithelial cells and type II pneumocytes of the epithelium. We have also found MAP3K19 to be expressed in multiple, primary NSCLC tumor samples, as well as human lung cancer cell lines, including A549. The kinase is transcriptionally upregulated in cells upon various types of cell stress, including oxidative, endoplasmic reticulum and osmotic stress.
    
    Methods:
    Using two different murine xenograft models, we assayed the role of MAP3K19 to inhibit the growth of either primary human NSCLC tumors and A549 cells using small molecule inhibitors.
    
    Results:
    The ability of i.v. injected A549 cells to colonize and grow in the lung was significantly reduced in mice that received orally administered, selective MAP3K19 inhibitors. Similar results were observed in a subcutaneous xenograft model, as A549 tumor cell growth was inhibited by both MAP3K19 antagonists and other standard of care kinase inhibitors. These studies also showed an additive anti-proliferative effect when gefitinib or sorafenib and MAP3K19 inhibitors were co-administered. Importantly, xenograft models using primary human NSCLC tumors implanted subcutaneously in immunodeficient mice showed a statistically significant inhibition of tumor growth when the mice were treated with the orally administered MAP3K19 antagonists. IHC analysis of the tumors showed that mice treated with the MAP3K19 inhibitors also had decreased levels of Ki-67, c-myc, p27 and phospho-Bim staining and increased caspase-3 staining.
    
    Conclusion:
    These results suggest a molecular mechanism by which MAP3K19 may inhibit tumor cell growth, and further suggest that inhibition of MAP3K19 either by itself or in combination with other therapies may represent a new avenue for the treatment of NSCLC. The clinical development of the MAP3K19 inhibitor is expected to initiate Phase I clinical trials in early 2017.