Junctional adhesion molecule-A is overexpressed in advanced multiple myeloma and determines response to oncolytic reovirus
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Kevin R. Kelly1, Claudia M. Espitia2, Weiguo Zhao2, Erik Wendlandt3, Guido Tricot3, Fenghuang Zhan3, Jennifer S. Carew4, Steffan T. Nawrocki2
1Anne Nohl Division of Hematology and Center for the Study of Blood Diseases, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
2Department of Medicine and The Institute for Drug Development, Cancer Therapy and Research Center at The University of Texas Health Science Center, San Antonio, TX, USA
3Division of Hematology, Oncology, and Blood and Marrow Transplantation, Department of Internal Medicine, University of Iowa, Iowa City, IA, USA
4Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA
Steffan T. Nawrocki, e-mail: [email protected]
Keywords: myeloma, reovirus, bortezomib, JAM-A, NOXA
Received: August 20, 2015 Accepted: September 19, 2015 Published: October 15, 2015
Despite the development of several new agents for multiple myeloma (MM) therapy over the last decade, drug resistance continues to be a significant problem. Patients with relapsed/refractory disease have high mortality rates and desperately need new precision approaches that directly target specific molecular features that are prevalent in the refractory setting. Reolysin is a proprietary formulation of reovirus for cancer therapy that has demonstrated efficacy in multiple clinical trials. Its selective effects against solid tumors have been largely attributed to RAS-mediated control of reovirus replication. However, the mechanisms regulating its preferential anti-neoplastic effects in MM and other hematological malignancies have not been rigorously studied. Here we report that the reovirus receptor, junctional adhesion molecule-A (JAM-A) is highly expressed in primary cells from patients with MM and the majority of MM cell lines compared to normal controls. A series of experiments demonstrated that JAM-A expression, rather than RAS, was required for Reolysin-induced cell death in MM models. Notably, analysis of paired primary MM specimens revealed that JAM-A expression was significantly increased at relapse compared to diagnosis. Two different models of acquired resistance to bortezomib also displayed both higher JAM-A expression and elevated sensitivity to Reolysin compared to parental cells, suggesting that Reolysin may be an effective agent for patients with relapsed/refractory disease due to their high JAM-A levels. Taken together, these findings support further investigation of Reolysin for the treatment of patients with relapsed/refractory MM and of JAM-A as a predictive biomarker for sensitivity to Reolysin-induced cell death.
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