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LMTK3 is essential for oncogenic KIT expression in KIT-mutant GIST and melanoma

Oncogene volume 38, pages 1200–1210 (2019)Cite this article

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Abstract

Certain cancers, including gastrointestinal stromal tumor (GIST) and subsets of melanoma, are caused by somatic KIT mutations that result in KIT receptor tyrosine kinase constitutive activity, which drives proliferation. The treatment of KIT-mutant GIST has been revolutionized with the advent of KIT-directed cancer therapies. KIT tyrosine kinase inhibitors (TKI) are superior to conventional chemotherapy in their ability to control advanced KIT-mutant disease. However, these therapies have a limited duration of activity due to drug-resistant secondary KIT mutations that arise (or that are selected for) during KIT TKI treatment. To overcome the problem of KIT TKI resistance, we sought to identify novel therapeutic targets in KIT-mutant GIST and melanoma cells using a human tyrosine kinome siRNA screen. From this screen, we identified lemur tyrosine kinase 3 (LMTK3) and herein describe its role as a novel KIT regulator in KIT-mutant GIST and melanoma cells. We find that LMTK3 regulated the translation rate of KIT, such that loss of LMTK3 reduced total KIT, and thus KIT downstream signaling in cancer cells. Silencing of LMTK3 decreased cell viability and increased cell death in KIT-dependent, but not KIT-independent GIST and melanoma cell lines. Notably, LMTK3 silencing reduced viability of all KIT-mutant cell lines tested, even those with drug-resistant KIT secondary mutations. Furthermore, targeting of LMTK3 with siRNA delayed KIT-dependent GIST growth in a xenograft model. Our data suggest the potential of LMTK3 as a target for treatment of patients with KIT-mutant cancer, particularly after failure of KIT TKIs.

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Acknowledgements

Thank you to Dr. Sebastian Bauer (West German Cancer Center, Essen, Germany) for generously providing KIT-mutant GIST cell lines. Thank you to Dr. Dirk Schadendorf (West German Cancer Center, Essen, Germany) for generously providing the MaMel (144aI) cell line. Deepest thanks to Arin McKinley, Diana Griffith, and Ashley Young for their technical and administrative support during the course of this study.

Financial support

L.R. Klug, A. Town, A.E. Bannon, and M.C. Heinrich were supported by VA Merit Review Grants 1I01BX000338-01 and 2I01BX000338-05. M.C. Heinrich was also supported by the GIST Cancer Research Fund and the Life Raft Group. L.R. Klug, W.H. Fleming, J.W. Tyner, and M.C. Heinrich were supported by the V Foundation for Cancer Research. J.W. Tyner was supported by the Leukemia & Lymphoma Society, Gabrielle’s Angel Foundation for Cancer Research, and the National Cancer Institute (5R00CA151457-04; 1R01CA183947-01). N. Javidi-Sharifi was supported by the Oregon Clinical and Translational Research Institute (OCTRI), grant number TL1 RR024159 from the National Center for Advancing Translational Sciences (NCATS), a component of the NIH, and NIH Roadmap for Medical Research.

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Authors and Affiliations

  1. Portland VA Health Care System, Portland, OR, USA

    Lillian R. Klug, Amber E. Bannon, Ajia Town & Michael C. Heinrich

  2. Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA

    Lillian R. Klug, Amber E. Bannon, Nathalie Javidi-Sharifi, Ajia Town, William H. Fleming, Jeffrey W. Tyner & Michael C. Heinrich

  3. Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, OR, USA

    Lillian R. Klug, Amber E. Bannon, Nathalie Javidi-Sharifi, Ajia Town, William H. Fleming, Jeffrey W. Tyner & Michael C. Heinrich

  4. Department of Pediatrics, Oregon Stem Cell Center, Oregon Health and Science University, Portland, OR, USA

    William H. Fleming

  5. Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, OR, USA

    Judy K. VanSlyke & Linda S. Musil

  6. Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA

    Jonathan A. Fletcher

  7. Department of Pediatrics, Brigham and Women’s Hospital, Boston, MA, USA

    Jonathan A. Fletcher

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  1. Lillian R. Klug
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Correspondence to Lillian R. Klug.

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Conflict of interest

MCH is a consultant for Novartis, Deciphera Pharmaceuticals, Blueprint Medicines, Ariad Pharmaceuticals, Bayer Pharmaceuticals, and Molecular MD. MCH has provided expert testimony and has a patent licensed to Novartis. MCH receives research support from Ariad, Deciphera, Blueprint Medicines and has equity interest in Molecular MD. JWT receives research support from Agios Pharmaceuticals, Array Biopharma, Aptose Biosciences, AstraZeneca, Constellation Pharmaceuticals, Genentech, Gilead, Incyte Corporation, Janssen Pharmaceutica, Seattle Genetics, Syros, Takeda Pharmaceutical Company and is a consultant for Leap Oncology.

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Klug, L.R., Bannon, A.E., Javidi-Sharifi, N. et al. LMTK3 is essential for oncogenic KIT expression in KIT-mutant GIST and melanoma. Oncogene 38, 1200–1210 (2019). https://doi.org/10.1038/s41388-018-0508-5

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