The novel ?2-selective proteasome inhibitor LU-102 decreases phosphorylation of I kappa B and induces highly synergistic cytotoxicity in combination with ibrutinib in multiple myeloma cells.

ABSTRACT: Proteasome-inhibiting drugs (PI) are gaining importance in hematologic oncology. The proteasome carries three proteolytically active subunits (?1, ?2, ?5). All established PI (bortezomib and carfilzomib), as well as experimental drugs in the field (dalanzomib, oprozomib, and ixazomib), by design target the rate-limiting ?5 subunit. It is unknown whether ?2-selective proteasome inhibition can also be exploited toward anticancer treatment. Combining PI with the pan B-cell-directed Bruton tyrosine kinase inhibitor ibrutinib appears a natural option for future improved treatment of multiple myeloma (MM) and B-cell lymphomas. However, bortezomib induces phosphorylation of I?B and activation of NF-?B in MM cells, while ibrutinib inhibits the I?B/NF-?B axis, suggesting antagonistic signaling. A ?2-selective proteasome inhibitor may lack such antagonistic signaling effects.We recently introduced LU-102, the first ?2-selective PI available for preclinical testing. We here compare bortezomib with carfilzomib and LU-102 in MM and MCL in vitro with regard to their effects on pI?B/NF-?B signaling and their cytotoxic activity in combination with ibrutinib.LU-102 reduced phosphorylation of I?B, in contrast to bortezomib and carfilzomib, and was a superior inhibitor of NF-?B activation in MM cells. This translated into highly synergistic cytotoxicity between LU-102 and ibrutinib, which was able to overcome BTZ resistance and CFZ resistance. By contrast, BTZ lacked consistent synergistic cytotoxicity with ibrutinib.Ibrutinib is highly synergistic with ?2-selective proteasome inhibition against MM and MCL in vitro. Novel ?2-selective proteasome inhibitors may be exploited to overcome bortezomib/carfilzomib resistance and boost the activity of BTK inhibitors against B-cell-derived malignancies.

SUBMITTER: Kraus J 

PROVIDER: S-EPMC4515249 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature