Anti-myeloma effects of ruxolitinib combined with bortezomib and lenalidomide: A rationale for JAK/STAT pathway inhibition in myeloma patients

Author(s)

de Oliveira, Mariana B. ; Fook-Alves, Veruska L. ; Eugenio, Angela I. P. ; Fernando, Rodrigo C. ; Sanson, Luiz Felipe G. ; de Carvalho, Mariana F. ; Braga, Walter M. T. ; Davies, Faith E. ; Colleoni, Gisele W. B.

• Document type: Journal article
• Source: Cancer Letters; v. 403, p. 206-215, SEP 10 2017.
• Web of Science Citations: 9

Abstract

JAK proteins have been linked with survival and proliferation of multiple myeloma (MM) cells; therefore, JAK inhibition could be a therapeutic strategy for MM. We evaluated JAK1 and JAK2 expression in MM patients and the effects of JAK/STAT pathway inhibition on apoptosis, cell cycle, gene and protein expression in RPMI-8226 and U266 MM cell lines. 57% of patients presented overexpression of JA1C2 and 27%, of JAK1. After treatment with ruxolitinib and bortezomib, RPMI-8226 and U266 presented 50% of cells in late apoptosis, reduction of anti-apoptotic genes expression and higher number of cells in SubGO phase. Co-culture with stromal cells protected RPMI-8226 cells from apoptosis, which was reversed by lenalidomide addition. Combination of ruxolitinib, bortezomib and lenalidomide induced 72% of cell death, equivalent to bortezomib, lenalidomide and dexamethasone, combination used in clinical practice. Many JAK/STAT pathway genes, after treatment, had their expression reduced, mainly in RPMI-8226, with insignificant changes in U266. In this scenario, JAK/STAT pathway could pose as a new therapeutic target to be exploited, since it is constitutively active and contributes to survival of MM tumor cells. (C) 2017 Elsevier B.V. All rights reserved. (AU)

• FAPESP's process: 10/17668-6 - Identification of biomarkers and possible therapeutical targets in B-cell lymphoproliferative disorders
• Grantee: Gisele Wally Braga Colleoni
• Support Opportunities: Research Projects - Thematic Grants