Researchers Discover Mutations Behind Resistance to PARP Inhibitors Like Lynparza

Researchers Discover Mutations Behind Resistance to PARP Inhibitors Like Lynparza
Scientists have found mutations in the poly ADP-ribose polymerase (PARP) gene that cause resistance to PARP inhibitor therapies — such as Lynparza (olaparib) — in a mouse model and in one patient with ovarian cancer, according to a recent study. Detection of these mutations could help physicians to predict which cancer patients are likely to develop a resistance to PARP inhibitors and to decide the best possible treatment. 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. PARP enzymes act as DNA damage sensors, binding to the sites of DNA damage and leading to its repair. Cancer cells that have defects in other DNA repair mechanisms — such as those with mutated BRCA tumor suppressor genes, which cause 5.8% to 24.8% of all ovarian cancer cases — rely on PARP to survive and proliferate. It is believed that PARP activity suppression leads to the accumulation of DNA damage and ultimately to the death of these cancer cells, making PARP inhibitors especially effective in patients with BRCA mutations. Most clinical PARP inhibitors were shown to cause cell death not only through blocking PARP activity, but also by trapping PARP at the sites of DNA damage, to which the enzyme binds. Lynparza, an oral inhibitor of PARP, was initially approved in 2014 as a maintenance
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