A new study has shown that dinaciclib disrupted homologous recombination function and led to cell death in multiple myeloma cell lines when combined with the PARP1/2 inhibitor ABT-888.
A new study has shown that dinaciclib, a small-molecule inhibitor of cyclin-dependent kinases 1, 2, 5, and 9, disrupted homologous recombination function and led to cell death in multiple myeloma cell lines when combined with the PARP1/2 inhibitor ABT-888.
In their study, David A. Alagpulinsa, of Central Arkansas Veterans Healthcare System, and colleagues used dinaciclib to disrupt BRCA1 and RAD51 functions, impairing the ability of the multiple myeloma cells to repair double-strand breaks via homologous recombination.
“This approach selectively sensitizes multiple myeloma cells to the PARP1/2 inhibitor ABT-888, in a manner that (based on similar synthetic lethality for other drug combinations) appears to be mediated by dinaciclib’s disruption of homologous recombination repair,” they wrote in Molecular Cancer Therapeutics. “Since cyclin-dependent kinases, PARP1 and homologous recombination are deregulated in multiple myeloma and have been designated as therapeutic targets, our findings provide a strong rationale for combining dinaciclib with PARP inhibitors in targeting multiple myeloma cells, and a basis for further investigations of their safety and efficacy in multiple myeloma patients.”
According to the study, early trials of dinaciclib had shown that dinaciclib was promising for the treatment multiple myeloma. In this study, Alagpulinsa and colleagues hypothesized that when combined with PARP1/2 inhibition, dinaciclib would disrupt homologous recombination repair leading to cell death.
In this analysis, the researchers first tested ABT-888 alone on myeloma cell lines and found that the inhibitor had no significant effect on cell viability. Dinaciclib affected both viability and colony formation in all cell lines tested. However, use of the two drugs together “produced synergistic effects of cell survival.”
Next, the researchers examined if the significant effects of dinaciclib plus ABT-888 may be a result of blockage of homologous recombination repair, indicated by levels of BRCA1 and RAD51 foci, that allows persistence of ABT-888 induced double-strand breaks. They measured levels of BRCA1 and RAD51 foci and Î³H2AX foci-a marker of double-strand breaks-and found that “dinaciclib prevented repair of ABT-888–induced DNA damage, thus significantly reducing the fraction of cells with ≥ 5 nuclear BRCA1 foci from 47% to 6% (P < .0001) and ≥ 5 nuclear RAD51 foci from 46% to 4% (P < .0001), while causing a marked increase in the fraction of cells with ≥ 5 nuclear Î³H2AX foci from 19% to 52% (P < .0001).”
Next, the researchers evaluated treatment with dinaciclib and ABT-888 in SCID mice with multiple myeloma xenografts. The mice were given ABT-888 50 mg/kg twice daily 5 days per week and/or dinaciclib 35 mg/kg twice per week. In the third week of treatment, treatment with dinaciclib alone resulted in a ninefold increase in tumor volume and combined treatment resulted in a 1.7-fold increase in tumor volume compared with a 19-fold increase in mice treated with ABT-888 alone.
“We have demonstrated in this study that the [cyclin-dependent kinase] inhibitor dinaciclib disrupts [homologous recombination] function and causes a contextual synthetic lethality of multiple myeloma cells when combined with the PARP1/2 inhibitor ABT-888, while sparing normal peripheral blood CD19+ B cells,” the researchers wrote.