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Junctional adhesion molecule-A is overexpressed in advanced multiple myeloma and determines response to oncolytic reovirus

2015; Impact Journals LLC; Volume: 6; Issue: 38 Linguagem: Inglês

10.18632/oncotarget.5753

1949-2553

Kevin R. Kelly, Claudia M. Espitia, Weiguo Zhao, Erik Wendlandt, Guido Tricot, Fenghuang Zhan, Jennifer S. Carew, Steffan T. Nawrocki,

Cell death mechanisms and regulation

// Kevin R. Kelly 1 , Claudia M. Espitia 2 , Weiguo Zhao 2 , Erik Wendlandt 3 , Guido Tricot 3 , Fenghuang Zhan 3 , Jennifer S. Carew 4 , Steffan T. Nawrocki 2 1 Anne Nohl Division of Hematology and Center for the Study of Blood Diseases, University of Southern California Keck School of Medicine, Los Angeles, CA, USA 2 Department 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 3 Division of Hematology, Oncology, and Blood and Marrow Transplantation, Department of Internal Medicine, University of Iowa, Iowa City, IA, USA 4 Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA Correspondence to: Steffan T. Nawrocki, e-mail: Nawrocki@uthscsa.edu Keywords: myeloma, reovirus, bortezomib, JAM-A, NOXA Received: August 20, 2015 Accepted: September 19, 2015 Published: October 15, 2015 ABSTRACT 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.