A cyclin-dependent kinase inhibitor, dinaciclib, impairs homologous recombination and sensitizes multiple myeloma cells to PARP inhibition

Poly(ADP-ribose) polymerases 1 and 2 (PARP1/2) are required for single-strand break repair, and their inhibition causes DNA replication-fork collapse and double-strand break (DSB) formation. These DSBs are primarily repaired via homologous recombination (HR), a high-fidelity repair pathway. Should HR be deficient, DSBs may be repaired via error-prone nonhomologous end-joining mechanisms, or may persist, ultimately resulting in cell death. Synthetic lethality thus exists between PARP and HR functions. Multiple myeloma (MM) cells are characterized by chromosomal instability and pervasive DNA damage, implicating aberrant DNA repair. Cyclin-dependent kinases (CDKs), upstream modulators of HR, are dysregulated in MM. Here we show that a CDK inhibitor, dinaciclib, impairs HR repair and sensitizes MM cells to the PARP1/2 inhibitor ABT-888. Dinaciclib abolishes ABT-888-induced BRCA1 and RAD51 foci and potentiates DNA damage, indicated by increased H2AX foci. Dinaciclib treatment reduces expression of HR-repair genes, including Rad51, and blocks BRCA1 phosphorylation, a modification required for HR repair, thus inhibiting HR repair of chromosomal DSBs. Co-treatment with dinaciclib and ABT-888 in vitro resulted in synthetic lethality of MM cells, but not normal CD19⁺ B cells, and slowed growth of MM xenografts in SCID mice almost two-fold. These findings support combining dinaciclib with PARP inhibitors for MM therapy.

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