In this preclinical research effort, Zhang and colleagues showed that various subunits of immunoproteasome are highly expressed in mantle-cell lymphoma (MCL) cells. In particular, expression of specific immunoproteasome subunits is correlated with the activity of carfilzomib––a novel second-generation proteasome inhibitor––in MCL cells. Both primary and established MCL cells with high expression of immunoproteasome subunits were more responsive to carfilzomib, even at low doses. Conversely, MCL cells with low or no expression of immunoproteasome subunits were highly resistant to carfilzomib. These data suggest that the immunoproteasome could serve as a biomarker for identifying patients who will benefit from carfilzomib therapy.

Because Bruton’s tyrosine kinase (BTK) is essential for B-cell lymphoma growth and survival, Zhang and colleagues combined ibrutinib, a novel BTK inhibitor, with carfilzomib to treat carfilzomib- resistant MCL cells. In the preclinical cell model, ibrutinib sensitized these MCL cells, overcoming carfilzomib resistance.

The study authors concluded the BTK inhibitor ibrutinib appears to overcome carfilzomib resistance in MCL cells, suggesting that ibrutinib offers a unique therapeutic approach. Based on these data, clinical trials of ibrutinib combined with carfilzomib in patients with relapsed or refractory MCL are warranted.

References:

Zhang L, Ou Z, Wang J, et al. Ibrutinib overcomes carfilzomib resistance in immunoproteasome-deficient mantle cell lymphoma. Blood. 2013;122. Abstract 3074.