Resistance to the
proteasome inhibitor bortezomib is an emerging clinical problem whose mechanisms have not been fully elucidated. We considered the possibility that this could be associated with enhanced
proteasome activity in part through the action of the
proteasome maturation protein (POMP).
Bortezomib-resistant myeloma models were used to examine the correlation between POMP expression and
bortezomib sensitivity. POMP expression was then modulated using genetic and pharmacologic approaches to determine the effects on
proteasome inhibitor sensitivity in cell lines and in vivo models. Resistant cell lines were found to overexpress POMP, and while its suppression in cell lines enhanced
bortezomib sensitivity, POMP overexpression in
drug-naive cells conferred resistance. Overexpression of POMP was associated with increased levels of nuclear factor (erythroid-derived 2)-like (NRF2), and NRF2 was found to bind to and activate the POMP promoter. Knockdown of NRF2 in
bortezomib-resistant cells reduced POMP levels and
proteasome activity, whereas its overexpression in
drug-naive cells increased POMP and
proteasome activity. The NRF2 inhibitor
all-trans-retinoic acid reduced cellular NRF2 levels and increased the anti-proliferative and pro-apoptotic activities of
bortezomib in resistant cells, while decreasing
proteasome capacity. Finally, the combination of
all-trans-retinoic acid with
bortezomib showed enhanced activity against primary patient samples and in a murine model of
bortezomib-resistant myeloma. Taken together, these studies validate a role for the NRF2/POMP axis in
bortezomib resistance and identify NRF2 and POMP as potentially attractive targets for chemosensitization to this
proteasome inhibitor.