title: Junctional adhesion molecule-A is overexpressed in advanced multiple myeloma and determines response to oncolytic reovirus.
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.
authors.affiliation: 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.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Kelly
authors.affiliation: 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.
authors.forename: Claudia M
authors.initials: CM
authors.lastname: Espitia
authors.affiliation: 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.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Division of Hematology, Oncology, and Blood and Marrow Transplantation, Department of Internal Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: Erik
authors.initials: E
authors.lastname: Wendlandt
authors.affiliation: Division of Hematology, Oncology, and Blood and Marrow Transplantation, Department of Internal Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: Guido
authors.initials: G
authors.lastname: Tricot
authors.affiliation: Division of Hematology, Oncology, and Blood and Marrow Transplantation, Department of Internal Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: Fenghuang
authors.initials: F
authors.lastname: Zhan
authors.affiliation: Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Carew
authors.affiliation: 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.
authors.forename: Steffan T
authors.initials: ST
authors.lastname: Nawrocki
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D000069286:Bortezomib / Q000494:pharmacology; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D009101:Multiple Myeloma / Q000235:genetics / Q000628:therapy* / Q000821:virology; D009154:Mutation; D050130:Oncolytic Virotherapy / Q000379:methods*; D034622:RNA Interference; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D012087:Reoviridae / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D015815:Cell Adhesion Molecules; C407243:F11R protein, human; D011956:Receptors, Cell Surface; D000069286:Bortezomib; D018631:ras Proteins
keywords: JAM-A; NOXA; bortezomib; myeloma; reovirus