RON kinase: A target for treatment of cancer-induced bone destruction and osteoporosis

Kelsi Andrade, Jaime Fornetti, Ling Zhao, Scott C. Miller, R Randall, Neysi Anderson, Susan E. Waltz, Mark McHale, Alana L. Welm

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Bone destruction occurs in aging and numerous diseases, including osteoporosis and cancer. Many cancer patients have bone osteolysis that is refractory to state-of-the-art treatments, which block osteoclast activity with bisphosphonates or by inhibiting the receptor activator of nuclear factor κB ligand (RANKL) pathway. We previously showed that macrophage-stimulating protein (MSP) signaling, which is elevated in about 40% of breast cancers, promotes osteolytic bone metastasis by activation of the MSP signaling pathway in tumor cells or in the bone microenvironment. We show that MSP signals through its receptor, RON tyrosine kinase, expressed on host cells, to activate osteoclasts directly by a previously undescribed pathway that is complementary to RANKL signaling and converges on protooncogene, non-receptor tyrosine kinase SRC (SRC). Genetic or pharmacologic inhibition of RON kinase blocked cancer-mediated bone destruction and osteoporosis in severalmouse models. Furthermore, the RON kinase inhibitor BMS-777607/ASLAN002 altered markers of bone turnover in a first-in-human clinical cancer study, indicating the inhibitor's potential for normalizing bone loss in patients. These findings uncover a new therapeutic target for pathogenic bone loss and provide a rationale for treatment of bone destruction in various diseases with RON inhibitors. 2017

Original languageEnglish (US)
Article numbereaai9338
JournalScience Translational Medicine
Volume9
Issue number374
DOIs
StatePublished - Jan 25 2017
Externally publishedYes

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Bone Neoplasms
Osteoporosis
Phosphotransferases
Bone and Bones
Osteoclasts
Therapeutics
Neoplasms
Osteolysis
Bone Remodeling
Diphosphonates
Receptor Protein-Tyrosine Kinases
Cytoplasmic and Nuclear Receptors
rice bran saccharide
Protein-Tyrosine Kinases
Breast Neoplasms
Neoplasm Metastasis
Ligands

ASJC Scopus subject areas

  • Medicine(all)

Cite this

RON kinase : A target for treatment of cancer-induced bone destruction and osteoporosis. / Andrade, Kelsi; Fornetti, Jaime; Zhao, Ling; Miller, Scott C.; Randall, R; Anderson, Neysi; Waltz, Susan E.; McHale, Mark; Welm, Alana L.

In: Science Translational Medicine, Vol. 9, No. 374, eaai9338, 25.01.2017.

Research output: Contribution to journalArticle

Andrade, K, Fornetti, J, Zhao, L, Miller, SC, Randall, R, Anderson, N, Waltz, SE, McHale, M & Welm, AL 2017, 'RON kinase: A target for treatment of cancer-induced bone destruction and osteoporosis', Science Translational Medicine, vol. 9, no. 374, eaai9338. https://doi.org/10.1126/scitranslmed.aai9338
Andrade, Kelsi ; Fornetti, Jaime ; Zhao, Ling ; Miller, Scott C. ; Randall, R ; Anderson, Neysi ; Waltz, Susan E. ; McHale, Mark ; Welm, Alana L. / RON kinase : A target for treatment of cancer-induced bone destruction and osteoporosis. In: Science Translational Medicine. 2017 ; Vol. 9, No. 374.
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