Great Expectations

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Science  16 Oct 2009:
Vol. 326, Issue 5951, pp. 340-341
DOI: 10.1126/science.326_340d

Two genetic mutations that in combination cause cell death, whereas each alone does not, are known as synthetically lethal. Fairly recently, the synthetic lethality notion has been applied to the search for anticancer drugs, to identify lethal combinations of drugs with specific tumorigenic mutations. The first targeted anticancer drugs to emerge from this approach were inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP). These drugs exploit the synthetically lethal interaction between PARP and the tumor suppressor genes breast cancer 1 (BRCA1) or BRCA2, which are involved in DNA double-strand break repair by homologous recombination. Mutations in the BRCA genes are associated with an increased risk of breast and ovarian cancer, and PARP inhibitors are currently showing great promise in the clinic. Another tumor suppressor gene, phosphatase and tensin homolog (PTEN), is one of the most frequently mutated genes in human cancers and has been implicated in genome stability. Now, Mendes-Pereira et al. have found a role for PTEN in homologous recombination, and they demonstrate the sensitivity of PTEN mutant tumor cells to PARP inhibitors. PTEN-deficient cells were also highly sensitive to PARP inhibitors. BRCA mutations are relatively infrequent and limited mainly to breast and ovarian cancers. This study suggests that PARP inhibitors may also be useful in a far broader range of cancers that involve PTEN mutations, such as lung and colorectal tumors and glioblastomas.

EMBO Mol. Med. 1, 315 (2009).

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