Abstract ES01-3: Targeting homologous recombination: Translational studies of CDK and PARP inhibitors
Authors: Shapiro GI 
Published: August 2014

Inhibition of poly (ADP-ribose) polymerase (PARP) causes the degeneration of single-strand DNA breaks to more lethal double-strand breaks (DSBs), and also traps PARP-DNA complexes, which must be repaired or bypassed by homologous recombination (HR). PARP inhibition therefore results in synthetic lethality in cells that have impaired HR, such as BRCA-deficient cells. In breast cancer, the primary activity of PARP inhibitor monotherapy has been in those cancers arising in BRCA carriers.

Several strategies to selectively disrupt HR in tumor cells and sensitize them to PARP inhibition are under development. One such strategy involves inhibition of cyclin-dependent kinase 1 (CDK1), a cell cycle kinase that controls the G2/M transition and mitotic progression. We have shown that BRCA1 is phosphorylated by CDK1 at S1497 and S1189/1191, and that these phosphorylation events are important for BRCA1 recruitment to sites of DNA damage. CDK1 inhibition disrupts BRCA1 function, both in S phase checkpoint control, as well as in HR repair, and sensitizes BRCA-proficient cells to PARP inhibition, as well as to cisplatin. Additionally, other CDK family members, including CDK2 and CDK9, activate additional components of the HR pathway, including proteins responsible for DNA end resection and RAD51 transcription. Consequently, HR-proficient triple-negative breast cancer cells can be sensitized to PARP inhibition by the CDK inhibitor dinaciclib, a potent CDK1/2/9 inhibitor, both in vitro and in in vivo patient-derived xenograft models. This work has been translated to clinical trial, in which the combination of dinaciclib and veliparib is under evaluation.

In addition to CDK inhibition, other strategies designed to target HR proficiency include inhibition of the proteasome, as well as inhibition of checkpoint kinase 1, WEE1 kinase, PI3-kinase and HSP90. These approaches may also re-sensitize BRCA-deficient breast cancer cells with acquired PARP inhibitor resistance to drug treatment. This may be especially true of HSP90 inhibition. We have recently described a novel mechanism of PARP inhibitor resistance involving the HSP90-mediated stabilization of a BRCA1 BRCT domain-mutated protein, which retains the capability to participate in RAD51 loading during HR. Resistance to PARP inhibition is reversed by combined HSP90/PARP inhibition.

The interaction of CDK family members with DNA repair pathways may also extend to CDK4 and non-homologous end joining (NHEJ). CDK4 inhibition produces potent G1 arrest, effectively removing HR as a repair pathway, which occurs during the S and G2 phases. Cells therefore become dependent upon NHEJ to repair both endogenous and exogenous damage. This biology suggests that combined CDK4 and DNA-dependent protein kinase catalytic subunit inhibition may also be a successful anticancer strategy.

In summary, inhibition of cell cycle kinases can be used to manipulate the activity of DNA repair pathways, creating exploitable cellular backgrounds that have increased sensitivity to DNA damaging agents. The selectivity of rationally designed combinations for transformed cells will require careful preclinical assessment. Nonetheless, cell cycle and DNA repair pathways are expected to yield multiple new strategies for breast cancer.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr ES01-3.