Proteomics

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27

Repurposing tofacitinib as an anti-myeloma therapeutic to reverse growth-promoting effects of the bone marrow microenvironment


ABSTRACT: The myeloma bone marrow microenvironment drives proliferation of malignant plasma cells and promotes resistance to therapy. Interleukin-6 (IL-6) and downstream JAK/STAT signaling are thought to be central components of these microenvironment-induced phenotypes. In a prior drug repurposing screen, we identified tofacitinib, a pan-JAK inhibitor FDA-approved for rheumatoid arthritis, as an agent that may reverse the tumor-stimulating effects of bone marrow mesenchymal stromal cells.Here, we validated both in vitro, in stromal-responsive human myeloma cell lines, and in vivo, in orthotopic disseminated murine xenograft models of myeloma, that tofacitinib showed both single-agent and combination therapeutic efficacy in myeloma models. Surprisingly, we found that ruxolitinib, an FDA-approved agent targeting JAK1 and JAK2, did not lead to the same anti-myeloma effects. Combination with a novel irreversible JAK3-selective inhibitor also did not rescue ruxolitinib effects. RNA-seq and unbiased phosphoproteomics revealed that marrow stromal cells drive a JAK/STAT-mediated proliferative program in myeloma plasma cells, and tofacitinib reversed the large majority of these pro-growth signals. Taken together, our results suggest that tofacitinib specifically reverses the growth-promoting effects of the tumor microenvironment through blocking an IL-6-mediated signaling axis. As tofacitinib is already FDA-approved, these results can be rapidly translated into potential clinical benefits for myeloma patients.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Homo sapiens  

TISSUE(S): Blood

DISEASE(S): Multiple Myeloma

SUBMITTER: Christine Lam  

LAB HEAD: Arun Paul Wiita

PROVIDER: PXD006581 | Pride | 2018-10-24

REPOSITORIES: Pride

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Publications

Repurposing tofacitinib as an anti-myeloma therapeutic to reverse growth-promoting effects of the bone marrow microenvironment.

Lam Christine C   Ferguson Ian D ID   Mariano Margarette C MC   Lin Yu-Hsiu T YT   Murnane Megan M   Liu Hui H   Smith Geoffrey A GA   Wong Sandy W SW   Taunton Jack J   Liu Jun O JO   Mitsiades Constantine S CS   Hann Byron C BC   Aftab Blake T BT   Wiita Arun P AP  

Haematologica 20180405 7


The myeloma bone marrow microenvironment promotes proliferation of malignant plasma cells and resistance to therapy. Activation of JAK/STAT signaling is thought to be a central component of these microenvironment-induced phenotypes. In a prior drug repurposing screen, we identified tofacitinib, a pan-JAK inhibitor Food and Drug Administration (FDA) approved for rheumatoid arthritis, as an agent that may reverse the tumor-stimulating effects of bone marrow mesenchymal stromal cells. Herein, we va  ...[more]

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