DNA repair pathways as targets for therapeutics
Graeme Smith
KuDOS Pharmaceuticals Ltd, Cambridge, UK
An important determinant of the susceptibility of cancer cells to DNA damaging anti-cancer therapeutics is the ability of the cells to repair the DNA damage inflicted upon them. It has therefore been proposed that inhibition of DNA repair processes could lead to the potential therapeutic endpoints of radio-and chemosensitization. Since tumour cells in general are genomically unstable and have defects in DNA damage responses, it has been argued (and proven in certain cases) that targeting DNA repair pathways may lead to a therapeutic index in tumour cells over “normal” cells. We have designed and developed novel, potent and specific inhibitors of the key DNA repair enzymes PARP-1, DNA-PK and ATM. PARP-1 plays an important regulatory role in the process of base excision repair and we and others have found that inhibiting PARP-1 causes sensitization to a wide range of chemotherapeutics. Moreover, PARP-1 inhibition has been found to be synthetically lethal with the homologous recombination repair pathway which includes the familial breast cancer gene products BRCA1 and BRCA2. PARP inhibitors are now in clinical trials to evaluate their potential to treat cancers defective in BRCA1/2. Two key kinases involved in the detection, signalling and repair of DNA double strand breaks (DSBs) are ATM (ataxia- telangiectasia mutated) and DNA-PK (DNA-dependent protein kinase). The serine/threonine protein kinase ATM responds to DNA DSB damage by signalling to key cell cycle and DNA-repair components. The structurally related enzyme DNA-PK also responds to DNA DSBs and is intimately involved in the repair of DNA DSBs by the process of non-homologous end joining (NHEJ). Inhibition of ATM or DNA-PK with small molecule inhibitors abrogates DNA damage signalling pathways and potentiates the cytotoxic effects of ionizing radiation and other classes of DNA DSB inducing agents. DNA-PK inhibition is also found to preferentially sensitise ATM defective cells to DNA DSB inducing agents. Our results to date support the further evaluation of these classes of molecules as potential agents for monotherapy in appropriate cancer genetic backgrounds or as chemo- or radio-sensitizers.
