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Novel bone morphogenetic protein receptor inhibitor JL5 suppresses tumor cell survival signaling and induces regression of human lung cancer

Oncogene volume 37, pages 3672–3685 (2018)Cite this article

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Abstract

BMP receptor inhibitors induce death of cancer cells through the downregulation of antiapoptotic proteins XIAP, pTAK1, and Id1-Id3. However, the current most potent BMP receptor inhibitor, DMH2, does not downregulate BMP signaling in vivo because of metabolic instability and poor pharmacokinetics. Here we identified the site of metabolic instability of DMH2 and designed a novel BMP receptor inhibitor, JL5. We show that JL5 has a greater volume of distribution and suppresses the expression of Id1 and pTak1 in tumor xenografts. Moreover, we demonstrate JL5-induced tumor cell death and tumor regression in xenograft mouse models without immune cells and humanized with adoptively transferred human immune cells. In humanized mice, JL5 additionally induces the infiltration of immune cells within the tumor microenvironment. Our studies show that the BMP signaling pathway is targetable in vivo and BMP receptor inhibitors can be developed as a therapeutic to treat cancer patients.

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Acknowledgements

This work utilized shared resources at Rutgers Cancer Institute of New Jersey, which are supported by NCI P30CA72720.

Author contributions:

J.L. and A.Z. designed the experiments, interpreted the data, and wrote the manuscript. J.H.N. performed in vivo experiments and interpreted the data. D.J.A. designed and synthesized JL5. R.N., E.L., C.B.C., N.S.D., M.J.L., S.T., S.R.J., P.K.B., S.M., and S.L. performed experiments. S.K.J. designed experiments. J.M. performed genetic alternations studies, M.G. interpreted toxicity studies, and M.O.C. performed blood chemistry studies. E.T.S. and C.M. evaluated and interpreted pathology data. J.E.K. designed BMP inhibitors. All authors contributed to writing and/or providing feedback on the manuscript.

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Author notes

  1. These authors contributed equally: Andrew Zloza and John Langenfeld.

Authors and Affiliations

  1. Section of Surgical Oncology Research, Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08903, USA

    Jenna H. Newman, Charles B. Chesson, Natalie S. Dobias, Praveen K. Bommareddy, Sh’Rae Marshall, Shengguo Li & Andrew Zloza

  2. Office of Translational Science, Molecular Design and Synthesis, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA

    David J. Augeri

  3. Department of Surgery, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, 08903, USA

    Rachel NeMoyer, Michael J. Lee, Saeed Tarabichi & Andrew Zloza

  4. Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08903, USA

    Jyoti Malhotra

  5. Department of Surgery, Division of Surgical Oncology and Thoracic Surgery, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08903, USA

    Elaine Langenfeld & John Langenfeld

  6. Department of Radiation Oncology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, 08903, USA

    Sachin R. Jhawar & Salma K. Jabbour

  7. Department of Pathology and Laboratory Science, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, 08903, USA

    Evita T. Sadimin, Christine Minerowicz & Mary O. Carayannopolous

  8. Department of Bioinformatics, Rutgers Biomedical Health Sciences, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA

    John E. Kerrigan

  9. Office of Translational Science, Research Pathology Services, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA

    Michael Goedken

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  1. Jenna H. Newman
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Correspondence to Andrew Zloza or John Langenfeld.

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J.L., D.J.A., and J.E.K. are inventors of pending patents related to this study. The remaining authors declare that they have no conflict of interest.

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Newman, J.H., Augeri, D.J., NeMoyer, R. et al. Novel bone morphogenetic protein receptor inhibitor JL5 suppresses tumor cell survival signaling and induces regression of human lung cancer. Oncogene 37, 3672–3685 (2018). https://doi.org/10.1038/s41388-018-0156-9

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