Study Discovers Mutations That Cause Resistance to Lynparza, Similar Therapies

Study Discovers Mutations That Cause Resistance to Lynparza, Similar Therapies
Researchers have identified mutations in the poly (ADP-ribose) polymerase (PARP) gene that cause resistance to the cancer therapy Lynparza (olaparib) and other PARP inhibitors.  These mutations could help physicians predict which cancer patients will respond to the therapy and who will likely become resistant. With this insight, doctors can decide the most appropriate treatment approach. The study, “Genome-wide and high-density CRISPR-Cas9 screens identify point mutations in PARP1 causing PARP inhibitor resistance,” was published in the journal Nature Communications. Lynparza, an oral medicine developed by AstraZeneca, is approved in the U.S for the treatment of HER2-negative, metastatic breast cancer patients who have mutations in the BRCA genes and have received prior chemotherapy treatment. The medicine is also approved as a maintenance treatment for advanced ovarian cancer. The compound is an inhibitor of PARP enzymes – particularly PARP1 – which are key factors for repairing DNA damage. Because it targets DNA-repairing proteins, the treatment is most effective in tumors that lack other DNA-repairing proteins, such as those with mutations in the BRCA genes. It is believed that suppressing PARP activity leads to the accumulation of DNA damage and ultimately to the death of these cancer cells. However, if cancer cells alter their PARP1 activity or structure, they will most likely become resistant to PARP inhibitors, as these treatments will no longer be able to eliminate the tumor. In a study funded by Cancer Research UK and Breast Cancer Now, researchers investigated the effects of PARP1 mutations and examined how these alterations could stop PARP inhibitors from being effective. "PARP inhibitors are hugely exciting new drugs w
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