PT  - JOURNAL ARTICLE
AU  - Christine Lam
AU  - Megan Murnane
AU  - Hui Liu
AU  - Geoffrey A. Smith
AU  - Sandy Wong
AU  - Jack Taunton
AU  - Jun O. Liu
AU  - Constantine S. Mitsiades
AU  - Byron C. Hann
AU  - Blake T. Aftab
AU  - Arun P. Wiita
TI  - Repurposing tofacitinib as an anti-myeloma therapeutic to reverse growth-promoting effects of the bone marrow microenvironment
AID  - 10.1101/143206
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 143206
4099  - http://biorxiv.org/content/early/2017/05/28/143206.short
4100  - http://biorxiv.org/content/early/2017/05/28/143206.full
AB  - The myeloma bone marrow microenvironment promotes proliferation of malignant plasma cells and 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 enhance ruxolitinib effects. RNA-seq and unbiased phosphoproteomics revealed that marrow stromal cells stimulate 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.