Clinically relevant pulse-treatment generates bortezomib-resistant myeloma cell line that lacks proteasome mutations and is sensitive to Bcl-2 inhibitor venetoclax

Abstract Proteasome inhibitors bortezomib and carfilzomib are the backbone of treatments of multiple myeloma, which remains uncurable despite many recent advances. With many patients relapsing despite high initial response rates to proteasome inhibitor-containing regimens, it is critical to understand the process of acquired resistance. In vitro generated resistant cell lines are important tools in this process. The majority of previously developed bortezomib-resistant cell lines bear mutations in the proteasome PSMB5 sites, the prime target of bortezomib and carfilzomib, which are rarely observed in patients. Here we present a novel bortezomib-resistant derivative of KMS-12-BM multiple myeloma cell line, KMS-12-BM-BPR. Unlike previously published bortezomib-resistant cell lines, this sub-line was created using a clinically relevant twice-weekly pulse treatments with bortezomib instead of continuous incubation. It does not contain mutations in proteasome active sites and retains its sensitivity to carfilzomib. Reduced load on proteasome due to decreased protein synthesis appears to be the main cause of resistance. In addition, KMS-12-BM-BPR cells express less Mcl-1 than wild type and are more sensitive to Bcl-2 inhibitor venetoclax. Overall, this study demonstrates the feasibility of creating a proteasome-resistant myeloma cell lines by using clinically relevant pulse treatments and provides a novel model of acquired resistance.