PARP inhibitor olaparib induces DNA damage and acts as a drug sensitizer in an in vitro model of canine hematopoietic cancer.

Abstract

BACKGROUND: The introduction of genetic tests based on next-generation sequencing techniques into veterinary cancer diagnostics provides information on molecularly targeted therapies useful for dogs. However, there is still a lack of in vitro studies describing the effect and mechanism of action of such anti-cancer drugs in companion animals. Our study aimed to demonstrate in vitro activity of a commonly used PARP inhibitor, olaparib, in canine lymphoma and leukemia cells as well as to indicate its potential uses in anti-cancer therapy based on the mutational status of DNA damage related genes. Canine lymphoma and leukemia cell lines were incubated with olaparib alone and in combination with doxorubicin, and the impact of a single drug and combinations on cell viability, proliferation, induction of apoptosis, and DNA damage were assessed. RESULTS: The study showed that olaparib acts as a single agent, inhibiting the metabolic activity of canine lymphoma (CLBL-1, CNK-89) and leukemia (CLB70, GL-1) cells, affecting cell proliferation rates and causing DNA damage. In the tested cells, olaparib also worked as a chemosensitizer, due to its ability to potentiate cytotoxic effects of doxorubicin. Finally, RNA-seq data identify various mutational burden differences in genes involved in the DNA damage response in CLBL-1 and GL-1 cell lines that may explain the observed in vitro sensitivity differences to olaparib. CONCLUSIONS: Olaparib may be an interesting oral therapy alternative to classic chemotherapy or adjuvant option in dogs with hematopoietic cancer with known DNA repair disorders.