Targeting DNA damage response in cancer therapy

Abstract

Cancer chemotherapy and radiotherapy are designed to kill cancer cells mostly by inducing DNA damage. DNA damage is normally recognized and repaired by the intrinsic DNA damage response machinery. If the damaged lesions are successfully repaired, the cells will survive. In order to specifically and effectively kill cancer cells by therapies that induce DNA damage, it is important to take advantage of specific abnormalities in the DNA damage response machinery that are present in cancer cells but not in normal cells. Such properties of cancer cells can provide biomarkers or targets for sensitization. For example, defects or upregulation of the specific pathways that recognize or repair specific types of DNA damage can serve as biomarkers of favorable or poor response to therapies that induce such types of DNA damage. Inhibition of a DNA damage response pathway may enhance the therapeutic effects in combination with the DNA-damaging agents. Moreover, it may also be useful as a monotherapy when it achieves synthetic lethality, in which inhibition of a complementary DNA damage response pathway selectively kills cancer cells that have a defect in a particular DNA repair pathway. The most striking application of this strategy is the treatment of cancers deficient in homologous recombination by poly(ADP-ribose) polymerase inhibitors. In this review, we describe the impact of targeting the cancer-specific aberrations in the DNA damage response by explaining how these treatment strategies are currently being evaluated in preclinical or clinical trials.

Keywords: Cancer therapy; DNA damage response; DNA repair; PARP inhibitors; synthetic lethality.

Fig. 1

Overview of the diverse spectrum of DNA damage and the DNA damage response. The major repair pathways and key proteins used to process each type of damage are shown. In non-homologous end-joining (NHEJ), the Ku70/Ku80 complex binds to the DNA double-strand break ends and recruits the other indicated components. In base-excision repair (BER), poly(ADP-ribose) polymerase-1 (PARP-1) detects and binds to single-strand breaks and ensures accumulation of other repair factors at the breaks. Single-strand breaks containing modified DNA ends are recognized by damage-specific proteins such as apurinic/apyrimidinic endonuclease (APE1), which subsequently recruits Polβ and XRCC1-DNA ligase IIIα to accomplish the repair. All the molecules indicated here are aberrated in sporadic cancers. The proteins targeted for cancer therapy in the present clinical trials are marked with red asterisks. alt-NHEJ, alternative NHEJ; ATM, ataxia telangiectasia mutated; ATR, ataxia telangiectasia and Rad3-related; FA, Fanconi anemia; HR, homologous recombination; MGMT, O⁶-methylguanine-DNA methyltransferase; MMR, mismatch repair; MRN, MRE11–RAD50–NBS1; NER, nucleotide excision repair; TLS, translesion synthesis.

Fig. 2

Early steps of homologous recombination. First, the DNA double-strand break is sensed by the MRE11–RAD50–NBS1 (MRN) complex, which subsequently recruits and activates the ataxia telangiectasia mutated (ATM) kinase. Then, the DNA ends are resected by the MRN complex and CtIP, resulting in generation of 3′ single-stranded DNA (ssDNA) overhangs on both sides of the break. These overhangs are coated and stabilized by replication protein A (RPA). Next, BRCA2, which forms the BRCA1–PALB2–BRCA2 complex, directly binds RAD51 and recruits it to the double-stranded DNA–ssDNA junction, and promotes the loading of RAD51 onto ssDNA. This step is followed by displacement of RPA from ssDNA ends and assembly of the RAD51–ssDNA filament, which is mediated by BRCA2, leading to strand invasion into an undamaged homologous DNA template. All the molecules indicated here are aberrated in sporadic cancers. None of the proteins indicated here are targeted for cancer therapy in the present clinical trials. P, phosphorylation.

Fig. 3

Principle of synthetic lethality. DNA damage is often processed by multiple DNA repair pathways. In the example shown here, pathways A and B are both intact in normal cells, whereas pathway A is defective in cancer cells. (a) In the absence of the pathway B inhibitor, cancer cells can survive, because the defect in pathway A is compensated by the alternative pathway B. (b) When the cells are treated with the pathway B inhibitor, both pathways will be blocked in cancer cells, which will result in cell death. However, normal cells will not be affected, because inhibition of pathway B will be compensated by pathway A.