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

Targeting the DDR in Cancer

The DNA damage response (DDR) encompasses the intricate network of cellular responses to DNA damage (Figure 2). Different exogenous and endogenous factors continuously generate an enormous diversity of damage to the DNA. Cells possess a diversity of sophisticated biological pathways to cope with this plethora of DNA lesions. In addition to DNA repair pathways, the DDR also encompasses cell cycle checkpoint control and cell death pathways. Several different DNA repair mechanisms exist to repair different subsets of DNA lesions. The cell cycle checkpoint machinery facilitates faithful repair by halting cell cycle progression until DNA integrity has been restored. Cell death mechanisms, such as apoptosis, come into action in the case of excessive or unrepairable DNA damage, in this way preventing genomic instability that might otherwise lead to cancer.

Figure 2.

DNA damage response. Endogenous en exogenous sources causing DNA damage trigger the DNA damage response. This response consists of the intricate network between cell cycle checkpoint control, DNA repair, transcriptional regulation or in case of excessive DNA damage programed cell death mechanisms.

Defects in certain DDR pathways, especially DNA repair, predispose to specific types of cancer.[15] For example, xeroderma pigmentosum (XP) patients are predisposed to develop skin cancer. This syndrome is caused by genetic defects that abrogate repair of UV induced DNA lesions by the nucleotide excision repair (NER) pathway. Furthermore, hereditary nonpolyposis colorectal cancer (HNPCC) is caused by a mismatch repair defect. In the rest of this review, we will mainly concentrate on the development of breast and ovarian cancer in carriers of BRCA1 or BRCA2 gene mutations. Mutations in BRCA1 or BRCA2 lead to a defective homologous recombination (HR) repair pathway that is involved in the repair of DNA double strand breaks (DSBs) (Figure 3). Latest research among BRCA1 and BRCA2 mutation carriers revealed that these genetic aberrations also predispose to prostate cancer and pancreatic cancer, although to a lesser extent.[16] Thus, knowledge of DDR mechanisms is very important for understanding the nature and biological development of the respective malignancy. On the other hand, knowledge of DDR components is also very important for understanding therapy responses, because many classical chemotherapies and radiotherapy induce DNA damage.[17] For example, anthracyclins inhibit the function of the topoisomerase 1 enzyme, resulting in DSB induction during the S phase of the cell cycle, alkylating agents (such as Cyclophosphamide) induce DNA base damages, Platinum drugs cause DNA cross-links and radiotherapy creates DSBs. Tumor cells, which have a higher proliferation rate than most healthy cells, have more difficulties dealing with these DNA damages and thus the success of these treatments is thought to depend mainly on this proliferation-specific cytotoxicity. These treatments often fail in the end because of side-effects caused by cytotoxicity of rapidly proliferating tissues such as mucosal layers and lymphoid tissue.

Figure 3.

Homologous recombination. Simplified schematic of homologous recombination mechanism. Upon double strand break induction BRCA1 promotes 5′ to 3′ end resection whereas 53BP1 prevents this. In S phase cells most breaks undergo end resection and are determined for homologous recombination repair (step 2). On the 3′ DNA overhang RAD51 protein filaments are formed. This is facilitated by BRCA2, PALB2 and other proteins (step 3). RAD51 coated single-stranded DNA pairs with homologous sequences on the sister chromatid (red strands) from where missing information is copied (step 4). DNA synthesis goes on until all missing information is copied and single-stranded DNA ends are ligated (step 5). Finally, the complex sister chromatid pairing is resolved and the double strand break is completely repaired (step 6). Proteins involved in step 4–6 are not represented in this schematic but defects may also contribute to impaired homologous recombination.

In addition to this increased sensitivity of tumors caused by high proliferation rates, specific DDR defects in tumors may also increase sensitivity to certain chemotherapies. Some examples include the use of anthracyclins or cross-linking agents in tumors having a defect in DSB repair mechanisms such as BRCA1/2 associated breast cancer. Importantly, one should be careful that the DDR defect is specific for the tumor and is not present in the normal cells of the body. For example, the use of DNA cross-linking agents (such as Platinum compounds) to treat tumors in Fanconi anemia (FA) patients could be fatal as the interstrand cross-link repair deficiency in these patients is present in every cell.