Defects in HR repair can result in an overreliance on the protein PARP1, which is responsible for repair of DNA single strand breaks by the base excision repair pathway. Unrepaired single-strand breaks are converted to double-strand breaks during replication and must be repaired by HR [25
]. Thus, treating cells that are defective in HR with PARP inhibitors results in a targeted killing of the defective cells, while cells with intact HR are capable of repair. Defects in breast cancer susceptibility proteins BRCA1 and BRCA2 (FANCD1) result in HR defects [28
]. Clinical trials investigating the effectiveness of PARP inhibitors against recurrent ovarian cancer have been promising, but rigorous stratification of tumors for HR status or “BRCA-ness” (defects in HR) is needed to identify the patients who are likely to benefit [29
]. Future clinical trials with PARP1 inhibitors in breast cancer may require combination therapies, evaluation of resistance, and identification of non-BRCA biomarkers [32
PARP1 Inhibition has also been shown to be selectively toxic to ATM-defective tumor cell lines in vitro
and to increase radiosensitivity of other ATM-proficient cell lines, including nonsmall-cell lung cancer, medulloblastoma, ependymoma, and high-grade gliomas [33
]. In addition, cell lines lacking functional Mre11 are sensitive to PARP1 inhibitors, strengthening the case for combined use of PARP1 inhibitors with inhibitors of the FA pathway [36
PTEN (phosphatase and tensin homolog) is a tumor-suppressor gene and one of the most commonly mutated genes in human tumor cells [38
] (see ). PTEN deficiency results in decreased expression of RAD51, which is required for homologous recombination [38
]. PTEN deficient tumors are thus candidates for targeted therapy by PARP1 inhibition [36
]. Although approximately 470,000 (48%) of 977,628 newly diagnosed cancers each year in the US may have PTEN defects, only a subset of these cancers will have PTEN mutations that result in homologous recombination defects and sensitivity to PARP inhibitors [28
]. Current studies are aimed at determining the relationship between PTEN loss, RAD51 expression, and PARP1 inhibitor sensitivity [36
]. Efforts to asses HR status to establish which PTEN mutations lead to an HR defect, and determining under what circumstances RAD51 expression could be used as a biomarker, will be useful to stratify and predict PARP1 inhibitor sensitivity.
Figure 2 PTEN defects in cancers. Types of cancer diagnosed annually in the US (orange oval), with the estimates for PTEN deficiencies shown in each type (blue oval). An unknown percentage of tumors with PTEN deficiencies will have a defect in homologous recombination (more ...)
Synthetic lethal interactions with the FA pathway have been explored. An siRNA-based screen of cells deficient in the Fanconi core complex protein, FANCG, showed that ATM, PARP1, NBS1, and PLK1 were among the genes with a synthetic lethal interaction [52
] (see ). The FA-ATM synthetic lethal relationship is particularly interesting since ATM deficiency has been reported in a subset of patients with hematological malignancies, including mantle cell lymphoma, chronic lymphocytic leukemia, and acute lymphoblastic leukemia [53
], making these potential targets for treatment with FA pathway inhibitors (see ).
Function and expression of genes synthetically lethal with FA.