Cancer cells with BRCA mutations have deficiencies in homologous recombination, and drugs to exploit those deficiencies have been developed and used successfully in clinical trials. Olaparib, a PARP1 inhibitor, shrunk or stopped the growth of tumors from breast, ovarian and prostate cancers caused by mutations in the BRCA1 or BRCA2 genes. BRCA1 and BRCA2 are necessary for DNA repair by homologous recombination. When BRCA1 or BRCA2 are absent, another type of DNA repair mechanism called base-excision repair usually compensates for the lack of DNA repair by homologous recombination. Base-excision repair uses the PARP1 protein. So cancer cells with BRCA deficiencies survive with only one DNA repair mechanism. When the PARP1 protein is inhibited, that second repair mechanism is also inhibited, DNA repair is drastically reduced, and the cell dies.
By stopping DNA repair in such a fashion, olaparib applies the concept of synthetic lethality to specifically target cancer cells. Exploiting synthetic lethality is a new direction in anti-cancer drug development. While PARP1 inhibitors represent a novel approach to cancer therapy, researchers have cautioned that they may prove insufficient for treating late-stage, metastatic cancers. Cancer cells can become resistant to a PARP1 inhibitor if they experience deletions of mutations in BRCA2. This undermines the drug's synthetic lethality by restoring cancer cells' ability to repair DNA by homologous recombination.
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