Pharmacogenomics and chemical library screens reveal a novel SCF^SKP2 inhibitor that overcomes Bortezomib resistance in multiple myeloma.

ABSTRACT: While clinical benefit of the proteasome inhibitor (PI) bortezomib (BTZ) for multiple myeloma (MM) patients remains unchallenged, dose-limiting toxicities and drug resistance limit the long-term utility. The E3 ubiquitin ligase Skp1-Cullin-1-Skp2 (SCF^Skp2) promotes proteasomal degradation of the cell cycle inhibitor p27 to enhance tumor growth. Increased SKP2 expression and reduced p27 levels are frequent in human cancers and are associated with therapeutic resistance. SCF^Skp2 activity is increased by the Cullin-1-binding protein Commd1 and the Skp2-binding protein Cks1B. Here we observed higher CUL1, COMMD1 and SKP2 mRNA levels in CD138⁺ cells isolated from BTZ-resistant MM patients. Higher CUL1, COMMD1, SKP2 and CKS1B mRNA levels in patient CD138⁺

SUBMITTER: Malek E 

PROVIDER: S-EPMC5339431 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature