Bortezomib-induced "BRCAness" sensitizes multiple myeloma cells to PARP inhibitors

Chromosomal instability is a defining feature of clonal myeloma plasma cells that results in the perpetual accumulation of genomic aberrations. In addition to its role in protein homeostasis, the ubiquitin-proteasome system is also involved in the regulation of DNA damage-repair proteins. In the present study, we show that proteasome inhibition induces a "BRCAness" state in myeloma cells (MM), with depletion of their nuclear pool of ubiquitin and abrogation of H2AX polyubiquitylation, an essential step for the recruitment of BRCA1 and RAD51 to the sites of DNA double-stranded breaks (DSBs) and the initiation of homologous recombination (HR)-mediated DNA repair. Inhibition of poly-ADP-ribose-polymerase 1 and 2 (PARP1/2) with ABT-888 induced transient DNA DSBs that were rapidly resolved and thus had no effect on viability of the MM cells. In contrast, cotreatment of MM cell lines and primary CD138(+) cells with bortezomib and ABT-888 resulted in the sustained accumulation of unrepaired DNA DSBs with persistence of unubiquitylated γH2AX foci, lack of recruitment of BRCA1 and RAD51, and ensuing MM-cell death. The heightened cytotoxicity of ABT-888 in combination with bortezomib compared with either drug alone was also confirmed in MM xenografts in SCID mice. Our studies indicate that bortezomib impairs HR in MM and results in a contextual synthetic lethality when combined with PARP inhibitors.