A Cyclin-Dependent Kinase Inhibitor, Dinaciclib, Impairs Homologous Recombination and Sensitizes Multiple Myeloma Cells to PARP Inhibition

Abstract

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 γH2AX 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 chromosome 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.

CDK12 Inhibition Reverses De Novo and Acquired PARP Inhibitor Resistance in BRCA Wild-Type and Mutated Models of Triple-Negative Breast Cancer

“…We reasoned that the transcriptional effects of dinaciclib we observed would severely impair HR, as reported in multiple myeloma cells (Alagpulinsa et al, 2016). To test this prediction, we assessed functional metrics of HR in BRCA wild-type TNBC cells.…”

CDK5 inhibition in�vitro and in vivo induces cell death in�myeloma and overcomes the obstacle of bortezomib resistance

“…Knockout of CDK5 by siRNA suppressed the viability of MM cells, all of which suggested that cdK5 plays a key role of the pathogenesis in MM and favors a solid clinical application significance for the current research. Dinaciclib, a small molecule inhibitor of CDK1/2/5/9, has been shown to interfere with DNA damage repair in MM cells (18) and suppress the proliferation of MM cells by inducing endoplasmic reticulum stress in a CDK1/5 dependent manner (19). However, the mechanism of its inhibition on MM cell viability remains to be further studied.…”

“…Dinaciclib is a specific inhibitor of CDK1/2/5/9. Pre-clinical and early clinical studies have confirmed that dinaciclib is a promising anti-myeloma drug (18)(19)(20). The purpose of this study is to further explore the influence of CDK5 expression on prognosis, bortezomib response in MM patients and to uncover the deep synergistic anti-myeloma mechanism of dinaciclib and bortezomib.…”

PARP inhibitors: Clinical utility and possibilities of overcoming resistance

“…Mechanistically, knockdown of CDK12 leads to the concomitant downregulation of DNA repair proteins (such as BRCA1, FANC1, and ATR) thereby artificially establishing a “BRCAness” phenotype [51]. In late 2016 two in vitro studies reported that pharmacological inhibition of CDK12 with Dinaciclib reverses acquired PARPi resistance [52, 53]. Increased expression of WEE1, another cell cycle regulator, promotes de-sensitization of PARPi [54].…”