Unravelling the mechanisms of drug resistance to proteasome inhibitors to optimize treatment in patients with multiple myeloma
Proteasome inhibitors (PIs) are a backbone of multiple myeloma (MM) treatment, yet clinically applicable markers of resistance to PIs remain largely elusive. This project uses CRISPR screens to better understand mechanisms of drug resistance to PIs. To identify genes involved in proteasome inhibitor response, we will perform genome-wide CRISPR knock-out and activation screens in MM cell lines. In addition, we will perform a novel CRISPR mutagenesis screen to map possible resistance mutations in the PI target gene PSMB5. These drug response mechanisms will be validated in MM patient samples obtained at different therapeutic phases to map all relevant markers for in vivo drug response. Finally, a CRISPR drop-out screen will identify new target genes whose inactivation may act synergistically with PIs. The results of this project will enable better stratification of patients with MM to allow optimal use of PIs and to identify agents acting synergistically with PIs.