Synthetic lethality--a new direction in cancer-drug development.

In this issue of the Journal, Fong et al. report the results of a phase 1 trial of a new cancer therapy involving 60 patients (ClinicalTrials.gov number, NCT00516373).1 Readers may be surprised by the editors’ decision to publish a small early-stage trial, but this trial not only reports important results — it also points to a new direction in the development of anticancer drugs. Modern cancerdrug discovery focuses on finding new therapies with few side effects by leveraging advances in the understanding of cancer biology, but barriers to success are substantial. The story behind the report by Fong et al. demonstrates one way forward. Creating drugs that selectively kill cancer cells without harming normal cells is notoriously difficult for several reasons. First, oncogenes that are overexpressed in cancer cells are usually identical to, or mutated in ways that make them only subtly different from, their normal counterparts. For this reason, the development of treatment specifically targeting oncogenes in tumors is difficult. Furthermore, the products of tumor-suppressor genes with low or absent activity in tumors as a result of mutation are elusive pharmacologic targets — it is hard to restore an absent activity pharmacologically. To circumvent these difficulties, the idea was advanced that synthetic lethality might be useful in cancer-drug discovery.2 Two genes are said to be in a synthetic lethal relationship if a mutation in either gene alone is not lethal but mutations in both cause the death of the cell. In applying synthetic lethality to the discovery of cancer drugs, a screening program is designed to reveal a target gene that, when mutated or chemically inhibited, kills cells that harbor a specific cancerrelated alteration, such as a mutated tumor-suppressor gene or an activated oncogene, but spares otherwise identical cells lacking the cancer-related alteration.3 When the screening program detects a gene that, when inhibited, acts together with the abnormal cancer gene to kill cancer cells, synthetic lethality is confirmed. Such a gene can then be the target for developing an anticancer drug. Two papers published together in 20054,5 showed how synthetic lethality could be applied to cells that are deficient in a DNA-repair pathway (Fig. 1). These articles built on the observation that loss of activity of the enzyme poly(adenosine diphosphate [ADP]–ribose) polymerase 1 (PARP1) in normal cells induces high levels of DNA damage repair through the homologous-recombination pathway (i.e., the repair of breaks in doublestranded DNA with the use of homologous DNA sequences on an undamaged chromosome).6 They hypothesized that deficient homologous recombination would be lethal to a cell lacking PARP1. BRCA1 and BRCA2 are tumor-suppressor genes that underlie high-penetrance, hereditary breast and ovarian carcinomas. The corresponding proteins are key participants in homologous recombination. As predicted by the hypothesis, smallmolecule inhibitors of PARP1 are toxic to cells deficient in BRCA1 or BRCA2, whereas cells in which BRCA1 or BRCA2 had been restored were less sensitive to the inhibitors, by orders of magnitude. PARP1 activity is required for base-excision repair, a DNA-damage repair pathway that recognizes and eliminates DNA bases damaged by oxidation in a process that occurs thousands of times during each normal cell cycle. The interplay between base excision repair and homologous re-