title: RON kinase: A target for treatment of cancer-induced bone destruction and osteoporosis.
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 proto-oncogene, non-receptor tyrosine kinase SRC (SRC). Genetic or pharmacologic inhibition of RON kinase blocked cancer-mediated bone destruction and osteoporosis in several mouse 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.
authors.affiliation: Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Kelsi
authors.initials: K
authors.lastname: Andrade
authors.affiliation: Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Jaime
authors.initials: J
authors.lastname: Fornetti
authors.affiliation: Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Department of Radiology and Imaging Sciences, Division of Radiobiology, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Scott C
authors.initials: SC
authors.lastname: Miller
authors.affiliation: Department of Orthopaedics, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: R Lor
authors.initials: RL
authors.lastname: Randall
authors.affiliation: Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Neysi
authors.initials: N
authors.lastname: Anderson
authors.affiliation: Department of Cancer and Cell Biology, University of Cincinnati and Cincinnati Veterans Affairs Medical Center, Cincinnati, OH 45267, USA.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Waltz
authors.affiliation: Aslan Pharmaceuticals, Singapore 089824, Singapore.
authors.forename: Mark
authors.initials: M
authors.lastname: McHale
authors.affiliation: Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA. alana.welm@hci.utah.edu.
authors.forename: Alana L
authors.initials: AL
authors.lastname: Welm
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D001842:Bone and Bones / Q000473:pathology*; D004967:Estrogens / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000473:pathology*; D010006:Osteoblasts / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism; D010024:Osteoporosis / Q000473:pathology*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D000090063:Proto-Oncogene Mas; D011728:Pyridones / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D016896:Treatment Outcome
chemical_list: D000631:Aminopyridines; D004967:Estrogens; C000715470:MAS1 protein, human; C550356:N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D011728:Pyridones; C080835:RON protein; D020794:Receptor Protein-Tyrosine Kinases