Bortezomib induced BRCAness sensitizes multiple myeloma cells to PARP inhibitors
Menée in vitro et à l'aide de xénogreffes, cette étude suggère l'intérêt du bortézomib, en combinaison avec des inhibiteurs de PARP, pour le traitement du myélome multiple
Chromosomal instability is a defining feature of clonal myeloma plasma cells resulting 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. Here 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 initiation of homology-mediated (HR) DNA repair. Inhibition of poly-ADP-ribose-polymerase (PARP) 1-2 with ABT-888 induced transient DNA-DSBs that were rapidly resolved and hence had no effect on MM cells viability. In contrast, co-treatment 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 to 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.