Ruxolitinib acts as a selective inhibitor of CaMKII-γ to impede the progression of Bortezomib-resistant multiple myeloma through AMPK-ULK1 axis-mediated autophagy pathway

Multiple myeloma (MM) has become the second most common hematologic malignancy. In recent years, the incidence rate of MM is increasing and the onset age of MM is ahead. Although proteasome inhibitors and other strategies play important roles in the treatment of MM, almost all patients develop resistance after treatment. Therefore, novel drug targets and innovative therapeutic strategies are greatly needed. Here, we identified calcium/calmodulin-dependent protein kinase II gamma (CaMKII-γ) as a potential therapeutic target for Bortezomib-resistant multiple myeloma (BRMM). Then mechanism exploration results showed that autophagy pathway via CaMKII-γ-AMPK-ULK1 axis mediated the progression of BRMM. Furthermore, we identified Ruxolitinib (IC ₅₀  = 109 nM) as a selective small-molecule inhibitor of CaMKII-γ through high-throughput screening (HTS). Ruxolitinib demonstrated significantly tumor-suppressive effects on BRMM both in vitro and in vivo via down-regulation of CaMKII-γ-AMPK-ULK1 axis-mediated autophagy pathway. Notably, the antit-umor effect of Ruxolitinib was comparable to that observed with genetic CaMKII-γ ablation, highlighting its potential as a novel therapeutic strategy for the treatment of BRMM.