Dual intracellular targeting by ruxolitinib and the Mcl-1 inhibitor S63845 in interleukin-6-dependent myeloma cells blocks

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Dual intracellular targeting by ruxolitinib and the Mcl-1 inhibitor S63845 in interleukin-6-dependent myeloma cells blocks in vivo tumor growthMultiple myeloma remains an incurable malignancy with most patients experiencing relapse despite the introduction of novel therapies.While the first monoclonal antibodies have been approved for the treatment of myeloma, small molecule inhibitors of signaling pathways are still investigational.Although the concept of Janus kinase (JAK)/signal transducer and activator of transcription (STAT)3 inhibition in myeloma has shown promising results in preclinical studies, the efficacy of JAK inhibitors as single agents seems to be limited.1 Ruxolitinib is a potent JAK1/2 inhibitor and approved for the treatment of patients with myeloproliferative disease and for graft-versus-host disease. 2 While it has activity as a single agent in multiple myeloma, the combination with the myeloid cell leukemia (Mcl)-1 protein inhibitor S63845 resulted in superior survival in a preclinical in vivo model.The results obtained in the INA-6 xenograft model strongly support evaluation of the combination of JAK and Mcl-1 inhibition in humans.The JAK/STAT3 pathway is activated by cytokines of the gp130 family including interleukin (IL)-6 as the most prominent member with an established pathophysiological role in multiple myeloma.3,4 Ruxolitinib phosphate