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

Jenna H. Newman, David J. Augeri, Rachel Nemoyer, Jyoti Malhotra, Elaine Langenfeld, Charles B. Chesson, Natalie S. Dobias, Michael J. Lee, Saeed Tarabichi, Sachin R. Jhawar, Praveen K. Bommareddy, Sh'Rae Marshall, Evita T. Sadimin, John E. Kerrigan, Michael Goedken, Christine Minerowicz, Salma K. Jabbour, Shengguo Li, Mary O. Carayannopolous, Andrew ZlozaJohn Langenfeld

Research output: Contribution to journalArticle

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3672-3685
Number of pages14
JournalOncogene
Volume37
Issue number27
DOIs
StatePublished - Jul 5 2018

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Newman, J. H., Augeri, D. J., Nemoyer, R., Malhotra, J., Langenfeld, E., Chesson, C. B., Dobias, N. S., Lee, M. J., Tarabichi, S., Jhawar, S. R., Bommareddy, P. K., Marshall, SR., Sadimin, E. T., Kerrigan, J. E., Goedken, M., Minerowicz, C., Jabbour, S. K., Li, S., Carayannopolous, M. O., ... Langenfeld, J. (2018). Novel bone morphogenetic protein receptor inhibitor JL5 suppresses tumor cell survival signaling and induces regression of human lung cancer. Oncogene, 37(27), 3672-3685. https://doi.org/10.1038/s41388-018-0156-9