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Homologous recombinant deficiency and PARP therapy

NextEdge Admin

30 Sep 2023

3 min 20 sec

Homologous recombination deficiency (HRD) is a term used to describe a specific genetic or molecular characteristic of cancer cells, particularly in the context of ovarian, breast, and other cancer types. HRD refers to a defect or impairment in the homologous recombination DNA repair pathway, which is responsible for repairing double-strand DNA breaks. When this pathway is compromised, cancer cells become more reliant on alternative DNA repair mechanisms, such as base excision repair. PARP (Poly ADP-Ribose Polymerase) therapy, often involving the use of PARP inhibitors, is a targeted cancer treatment strategy that exploits HRD in cancer cells. Here’s how HRD and PARP therapy are related:

HRD in Cancer Cells: HRD can result from genetic mutations or alterations in genes involved in homologous recombination repair, such as BRCA1 and BRCA2. These mutations disrupt the cell’s ability to repair double-strand DNA breaks accurately.
PARP Inhibition: PARP inhibitors are drugs that specifically target the PARP enzymes. PARP enzymes play a role in repairing single-strand DNA breaks. When PARP inhibitors are introduced into cancer cells with HRD (such as those with BRCA mutations), they inhibit the repair of single- strand DNA breaks, further disrupting the cell’s DNA repair mechanisms.

Synthetic Lethality: The combination of HRD and PARP inhibition leads to synthetic lethality. In cells with HRD (e.g., BRCA-mutated cancer cells), blocking PARP prevents the repair of single-strand DNA breaks. Since these cells are already deficient in homologous recombination repair, they are unable to fix the accumulating DNA damage efficiently. This eventually results in cell death.
Selective Toxicity: PARP inhibitors exhibit selective toxicity towards cancer cells with HRD while sparing normal cells with functional DNA repair mechanisms. This selectivity makes PARP inhibitors a promising and targeted approach to cancer therapy.
Clinical Use: PARP inhibitors are used primarily in the treatment of certain types of cancer, such as ovarian and breast cancer, especially in cases where there is known HRD, such as BRCA mutations. They have also shown promise in other cancer types, including prostate cancer.