Tesaro (niraparib) and Lymparza (olaparib) — both PARP1 inhibitors approved by the U.S. Food and Drug Administration to treat breast and ovarian cancer patients — also kill malignant pleural mesothelioma (MPM) cells, a new in vitro study finds.
The study, “Synthetic lethality in malignant pleural mesothelioma with PARP1 inhibition,” appeared in the journal Cancer Chemotherapy and Pharmacology.
MPM is an aggressive tumor for which therapeutic options remain limited. Tumors are often inoperable and respond poorly to current chemotherapy and radiation therapy. Previous studies reported that 23 to 64 percent of MPM patients carry mutations in a gene called BAP1 (BRCA1-associated protein 1).
This phenomenon is also observed in other cancers, including renal cell carcinomas, and cholangiocarcinoma (bile duct cancer).
BAP1 is part of a mechanism called homologous recombination (HR) DNA double strand breaks. Cells often use this to repair breaks in their DNA. This means that cells with mutations in the BAP1 gene have a defective HR pathway, relying on other DNA repair pathways. One such pathway is controlled by the PARP1 gene.
Researchers at the University of Florida in Gainesville hypothesized that BAP1-mutant MPM cells are defective in HR DNA repair, and would depend on PARP1 activity to proliferate.
They tested their hypothesis using two clinical PARP1 inhibitors – Tesaro and Lynparza – and investigated whether they could induce the death of MPM cells. Results showed that both drugs were toxic to all cell lines used in the study. But surprisingly, the toxicity of the PARP1 inhibitors was independent of BAP1 mutations, suggesting that PARP1-mediated DNA repair is critical for the survival of MPM cells.
“PARP1 inhibition at clinically relevant concentrations resulting in significant cytotoxicity in MPM demonstrates that agents such as olaparib and niraparib are promising for use in the treatment of MPM, for which effective treatment is desperately needed,” the study concluded. “Thus, clinical trials of PARP inhibitors in this difficult to treat malignancy would be warranted.”