Targeting of SKP2 to combat drug resistance in multiple myeloma

Multiple myeloma (MM) is an incurable plasma cell malignancy in which drug resistance remains a significant limitation to treatment. SKP2, the substrate-recognition component of the SCF-SKP2 ubiquitin-protein ligase complex, plays a critical role in the progression of various cancers, including MM. Targeting SKP2 as a therapeutic strategy offers a promising avenue for combating drug resistance in myeloma. Here, we show that SKP2 expression increases as the disease progresses from pre-myeloma to newly diagnosed and relapsed stages. Gene set enrichment analysis (GSEA) and immunoblotting further revealed that SKP2 inhibition by the preclinical chemical inhibitor SkpinC1 leads to decreased STAT3 inflammatory signalling and c-MYC expression in myeloma cells. When tested in SKP2-overexpressing cells, SkpinC1 retained the ability to reduce activated STAT3, c-MYC, and c-MAF protein levels to impair cell growth and induce apoptosis. Furthermore, SkpinC1 synergistically enhanced the sensitivity of patient myeloma samples to bortezomib. Taken together, these findings underline the potential of SKP2 inhibition to overcome drug resistance in MM.