PARP Inhibitors Destroy Cisplatin-Resistant Lung Cancer Cells

After relapse from treatment with the chemotherapeutic drug cisplatin, some types of cancer cells become dependent on the activity of the enzyme PARP1 (poly (ADP-ribose) polymerase1), which renders them susceptible to attack by the new generation of PARP inhibitors.

PARP enzymes are essential in a number of cellular functions, including expression of inflammatory genes. This protein is found in the nucleus of cells where its primary function is to detect and signal single-strand DNA breaks (SSB) to the enzyme mechanisms involved in SSB repair. PARP activation is an immediate cellular response to metabolic, chemical, or radiation-induced DNA SSB damage. Once PARP detects a SSB, it binds to the DNA, and, after a structural change, begins the synthesis of a poly (ADP-ribose) (PAR) chain as a signal for the other DNA-repairing enzymes. After completing the repair, the PAR chains are degraded via poly (ADP-ribose) glycohydrolase (PARG).

Investigators at University Paris Descartes (Paris, France) used non-small-cell lung cancer (NSCLC) cells to study the role of PARP1 in the aftermath of cisplatin treatment. They chose this model system because NSCLC is the leading cause of cancer-related morbidity and mortality worldwide, and patients with NSCLC are frequently treated with cisplatin.

They reported in the April 1, 2013, issue of the journal Cancer Research that PARP1 was highly expressed and constitutively hyperactivated in a majority of human cisplatin-resistant cancer cells. Cells manifesting elevated intracellular levels of poly(ADP-ribosyl)ated (PAR) proteins responded to pharmacologic PARP inhibitors as well as to PARP1-targeting siRNAs (small interfering RNAs) initiating a DNA damage response that translated into cell death following the activation of the intrinsic pathway of apoptosis. Complementing the findings in NSCLC, hyperactivated PARP1 was detected in cisplatin-resistant mesothelioma, ovarian cancer, and cervical cancer cell lines.

PARP1-overexpressing NSCLC tumor cells and xenografts displayed elevated levels of PAR, which predicted the response to PARP inhibitors in vitro and in vivo more accurately than PARP1 expression itself.

"Cisplatin is one of the most widely used conventional, anticancer chemotherapy drugs," said senior author Dr. Guido Kroemer, professor of medicine at University Paris Descartes. "Unfortunately, most patients respond only transiently to cisplatin therapy because their cancer cells develop ways to resist the effects of the drug. Our data show that in most cases, cisplatin resistance is linked to stereotyped biochemical changes in cancer cells that render them vulnerable to PARP inhibitors. This has clear implications for new treatment regimens and for developing biomarkers of response to cisplatin. We are following up these exciting clinical possibilities in our laboratory."

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