Bortezomib- and Carfilzomib-Resistant Multiple Myeloma Cells Generated in Vitro Match the Molecular Hallmarks of Bortezomib-Resistant Primary Myeloma Cells, but Differ in Their Sensitivity to Bortezomib, Carfilzomib and Novel Proteasome Inhibiting Drugs

Bortezomib (BTZ)-resistant multiple myeloma (MM) cells generated in vitro by low concentration drug exposure (BTZ-adapted cells) are a widely used model for proteasome inhibitor (PI) resistance, and proteasome 5 active site mutations were implicated as resistance mechanism. BTZ-resistant, patient-derived MM cells lack such mutations. Their BTZ resistance is putatively mediated by downregulation of IRE-1/sXBP-1 pathway. We investigated if the in vitro model of PI-adapted MM is consistent with these hallmarks of primary MM cells, and compared BTZ- or CFZ-adapted MM cells regarding their patterns of adaptive changes and sensitivity against next generation PI (ixazomib – IXA, delanzomib – DLZ, oprozomib – OPR, the 2 selective inhibitor LU-102 and two novel 5/2-targeted PI).