Abstract
Bruton’s tyrosine kinase (Btk) modulates B-cell development and activation and has an important role in antibody production. Interestingly, Btk may also affect human osteoclast (OC) function; however, the mechanism was unknown. Here we studied a potent and specific Btk inhibitor, CC-292, in multiple myeloma (MM). In this report, we demonstrate that, although CC-292 increased OC differentiation, it inhibited OC function via inhibition of c-Src, Pyk2 and cortactin, all involved in OC-sealing zone formation. As CC-292 did not show potent in vitro anti-MM activity, we next evaluated it in combination with the proteasome inhibitor, carfilzomib. We first studied the effect of carfilzomib on OC. Carfilzomib did not have an impact on OC-sealing zone formation but significantly inhibited OC differentiation. CC-292 combined with carfilzomib inhibited both sealing zone formation and OC differentiation, resulting in more profound inhibition of OC function than carfilzomib alone. Moreover, the combination treatment in an in vivo MM mouse model inhibited tumor burden compared with CC-292 alone; it also increased bone volume compared with carfilzomib alone. These results suggest that CC-292 combined with carfilzomib augments the inhibitory effects against OC within the bone microenvironment and has promising therapeutic potential for the treatment of MM and related bone disease.
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Acknowledgements
This work was supported by Onyx Pharmaceuticals Inc (South San Francisco, CA, USA) and the Proteasome Research and Integrative Science for Multiple Myeloma—Onyx Novel Therapies Program (PRISM—NTP). NS Raje is a recipient of the Leukemia & Lymphoma Society clinical scholar Award.
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EE, JS and WFW are employees and shareholders in Celgene Avilomics Research. SA-K and CJK are employees of Onyx Pharmaceuticals Inc. NSR is on the advisory boards of Celgene, Novartis, Millennium, Onyx and Amgen. NSR has received research funding from AstraZeneca, Eli Lilly and Acetylon Pharmaceuticals.
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HE designed the research, performed the experiments, collected, analyzed and interpreted the data, and wrote the manuscript. LS performed the experiments, collected and analyzed the data and helped with writing the manuscript. DDC, AJY, TAS, NN, YM and PRW performed the research and collected the data. SA-K, EE, JS, CJK and WFW provided compounds. NSR designed the research, provided the environment and support, and wrote the manuscript.
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Eda, H., Santo, L., Cirstea, D. et al. A novel Bruton’s tyrosine kinase inhibitor CC-292 in combination with the proteasome inhibitor carfilzomib impacts the bone microenvironment in a multiple myeloma model with resultant antimyeloma activity. Leukemia 28, 1892–1901 (2014). https://doi.org/10.1038/leu.2014.69
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DOI: https://doi.org/10.1038/leu.2014.69
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