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 Zloza; John Langenfeld

doi:10.1038/s41388-018-0156-9

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

Journal article

Peer reviewed

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, …

Oncogene, Vol.37(27), pp.3672-3685

07/2018

DOI: https://doi.org/10.1038/s41388-018-0156-9

PMID: 29622797

Abstract

Lung Neoplasms - drug therapy

Pyrazoles - therapeutic use

Humans

Lung Neoplasms - pathology

Quinolones - pharmacology

Adoptive Transfer

Pyrimidines - chemistry

Bone Morphogenetic Protein Receptors - antagonists & inhibitors

Inhibitor of Differentiation Protein 1 - biosynthesis

Protein Kinase Inhibitors - chemistry

Pyrazoles - chemistry

Quinolones - chemistry

Quinolones - therapeutic use

Antineoplastic Agents - pharmacology

Pyrazoles - pharmacology

Carcinoma, Non-Small-Cell Lung - pathology

Tumor Microenvironment - drug effects

A549 Cells

Cell Survival - drug effects

Pyrimidines - pharmacology

Antineoplastic Agents - chemistry

Mice, SCID

Xenograft Model Antitumor Assays

Animals

MAP Kinase Kinase Kinases - biosynthesis

Signal Transduction - drug effects

Pyrimidines - therapeutic use

Cell Line, Tumor

Mice, Inbred NOD

Mice

Protein Kinase Inhibitors - pharmacology

Carcinoma, Non-Small-Cell Lung - drug therapy

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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Title: Novel bone morphogenetic protein receptor inhibitor JL5 suppresses tumor cell survival signaling and induces regression of human lung cancer
Creators: Jenna H Newman - Section of Surgical Oncology Research, Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08903, USA
David J Augeri - Office of Translational Science, Molecular Design and Synthesis, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
Rachel NeMoyer - Department of Surgery, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, 08903, USA
Jyoti Malhotra - Division of Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08903, USA
Elaine Langenfeld - Department of Surgery, Division of Surgical Oncology and Thoracic Surgery, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08903, USA
Charles B Chesson - Section of Surgical Oncology Research, Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08903, USA
Natalie S Dobias - Section of Surgical Oncology Research, Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08903, USA
Michael J Lee - Department of Surgery, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, 08903, USA
Saeed Tarabichi - Department of Surgery, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, 08903, USA
Sachin R Jhawar - Department of Radiation Oncology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, 08903, USA
Praveen K Bommareddy - Section of Surgical Oncology Research, Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08903, USA
Sh'Rae Marshall - Section of Surgical Oncology Research, Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08903, USA
Evita T Sadimin - Department of Pathology and Laboratory Science, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, 08903, USA
John E Kerrigan - Department of Bioinformatics, Rutgers Biomedical Health Sciences, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
Michael Goedken - Office of Translational Science, Research Pathology Services, Rutgers, The State University of New Jersey, Piscataway, NJ, 08854, USA
Christine Minerowicz - Department of Pathology and Laboratory Science, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, 08903, USA
Salma K Jabbour - Department of Radiation Oncology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, 08903, USA
Shengguo Li - Section of Surgical Oncology Research, Division of Surgical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08903, USA
Mary O Carayannopolous - Department of Pathology and Laboratory Science, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, 08903, USA
Andrew Zloza - Department of Surgery, Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, 08903, USA. andrew.zloza@rutgers.edu
John Langenfeld - Department of Surgery, Division of Surgical Oncology and Thoracic Surgery, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, 08903, USA. langenje@cinj.rutgers.edu
Publication Details: Oncogene, Vol.37(27), pp.3672-3685
Date published: 07/2018
Grant note: P30CA72720 / NIH HHS
Academic Unit: Medicinal Chemistry (EMSOP); Clinical Radiation Oncology; Rutgers Translational Sciences; Graduate School of Biomedical Sciences - Newark; Pathology and Laboratory Medicine (RWJMS); Surgery - Cardiothoracic Surgery (RWJMS); Lung Cancer/Thoracic Oncology Program; Pathology
Language: English
Resource Type: Journal article
Identifiers: 991031654815304646