Abstract
Proteasome inhibitor (PI) carfilzomib (CFZ) has activity superior to bortezomib (BTZ) and is increasingly incorporated in multiple myeloma (MM) frontline therapy and relapsed settings. Most MM patients ultimately experience PI-refractory disease, an unmet medical need with poorly understood biology and dismal outcome. Pharmacologic targeting of ABCB1 improved patient outcomes, including MM, but suffered from adverse drug effects and insufficient plasma concentrations. Proteomics analysis identified ABCB1 overexpression as the most significant change in CFZ-resistant MM cells. We addressed the functional role of ABCB1 overexpression in MM and observed significantly upregulated ABCB1 in peripheral blood malignant plasma cells (PCs) vs untreated patients’ bone marrow PC. ABCB1 overexpression reduces the proteasome-inhibiting activity of CFZ due to drug efflux, in contrast to BTZ. Likewise, the cytotoxicity of established anti-MM drugs was significantly reduced in ABCB1-expressing MM cells. In search for potential drugs targeting ABCB1 in clinical trials, we identified the HIV protease inhibitors nelfinavir (NFV) and lopinavir (LPV) as potent functional modulators of ABCB1-mediated drug export, most likely via modulation of mitochondria permeability transition pore. NFV and LPV restored CFZ activity at therapeutically relevant drug levels and thus represent ready-to-use drugs to be tested in clinical trials to target ABCB1 and to re-sensitize PC to established myeloma drugs, in particular CFZ.
Highlights
Treatment regimens based on proteasome inhibitors (PIs) or immunomodulatory drugs are the current backbone of multiple myeloma (MM) therapy.[1]
Consistent with this, upregulation of ABCB1, and ABCG2, was observed in a set of paired MM samples isolated from a MM patient initially responding to CFZ-based therapy and later progressing to PC leukemia (PCL) under such therapy (baseline sample taken before initiating CFZbased therapy, second sample obtained during consecutive disease progression of the same patient under CFZ/dexamethasone therapy (Figure 1d))
Gene expression analysis before therapy from a patients cohort enrolled in ‘Total Therapy’ revealed that ABCB1 was significantly increased in CD138+ circulating peripheral blood (PB)–plasma cells (PCs) of 44 newly diagnosed patients with primary PCL, compared with CD138+ bone marrow PC from 617 treatment-naive patients (Figure 1e)
Summary
Treatment regimens based on proteasome inhibitors (PIs) or immunomodulatory drugs are the current backbone of multiple myeloma (MM) therapy.[1]. After initial approval of CFZ for MM treatment in the relapsed/refractory setting, its approval advanced to second line therapy together with lenalidomide/dexamethasone and it is increasingly incorporated into frontline MM treatments in clinical trials.[4,5]
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call