PARP Inhibitors: The Journey From Research Hypothesis to Clinical Approval

Kishan AT Naipal; Dik C van Gent


Personalized Medicine. 2015;12(2):139-154. 

In This Article

Sensitizing Tumors for PARP Inhibitors

The number of HR-deficient tumors that would benefit from PARP inhibitor treatment is relatively low, at this moment primarily the BRCA mutated breast and ovarian tumors. However, the utility of these inhibitors may be increased drastically if one could generate an HR-deficient state in tumor cells. One possible way of achieving this is by applying hyperthermia, an increase of temperature above 37°C. This treatment sensitizes cells to radiotherapy and is being validated in clinical setting now.[82,83] The mechanism depends in part on inhibition of DSB repair, especially HR.[84,85] This hyperthermia induced HR-deficiency is thought to be the result of proteasomal degradation of BRCA2, which also sensitizes tumor cells to PARP inhibitors.[86] Obviously, this strategy can only be applied to solid tumors that are easily accessible for hyperthermia treatment. The optimization of hyperthermia techniques to achieve effective heating of solid tumor areas is ongoing and holds great promise.[87] Furthermore, the use of PARP inhibitors instead of, or in combination with, radiation therapy after hyperthermia is under investigation and can be expected to boost the effectiveness of PARP inhibitors, also for treatment of HR-proficient tumors.

Another recent discovery claims that histone deacetylase inhibitors (HDACi) increase the sensitivity of certain tumor cells to PARP inhibitors.[88,89] These research groups have shown that the treatment with HDACi downregulates gene expression of BRCA1, BRCA2, ATR and CHK1. Furthermore, functionally the formation of RAD51 foci in response to DNA damage is reduced in HDACi treated cells suggesting an induced HR deficiency. PARP inhibitor treatment after prior HDACi treatment induced significantly more ?H2AX foci and resulted in more cell death in several ovarian cancer cell lines and triple negative breast cancer cell lines.[88,89] Thus, HDACi treatment might also sensitize HR-proficient tumors to PARP inhibitors; however, the clinical significance and exact mechanism of this are still under investigation. Importantly, it has not been investigated whether normal tissue, for example, intestinal mucosal lining and hematopoietic cells, are also sensitized by HDACi. This is crucial to predict adverse effects of this treatment.