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Cancer Lett. 2017 Sep 10;403:206-215. doi: 10.1016/j.canlet.2017.06.016. Epub 2017 Jun 20.

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

Author information

1
Clinical and Experimental Oncology Department, Federal University of São Paulo, UNIFESP, Brazil.
2
Winthrop P. Rockefeller Cancer Institute at UAMS, Little Rock, AR, USA.
3
Clinical and Experimental Oncology Department, Federal University of São Paulo, UNIFESP, Brazil. Electronic address: gcolleoni@unifesp.br.

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 JAK2 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 SubG0 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.

KEYWORDS:

JAK/STAT; JAK1; JAK2; Multiple myeloma; Ruxolitinib; Small molecule inhibitor

PMID:
28645562
DOI:
10.1016/j.canlet.2017.06.016
[Indexed for MEDLINE]

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