PARP inhibitors may beat cisplatin resistance in lung cancer
People with non-small cell lung cancer (NSCLC) who become resistant to the widely used chemotherapy drug cisplatin may be able to counteract this problem with the use of agents that target the protein poly (ADP-ribose) polymerase 1 (PARP1), investigators have found.
The study by Guido Kroemer, MD, PhD, of the University Paris Descartes in Paris, France, and colleagues revealed that NSCLC cell lines resistant to cisplatin had high PARP1 levels, and that the PARP1 was hyperactivated. The cell lines also displayed elevated amounts of poly (ADP-ribosyl), or PAR.
When the cell lines with high levels of hyperactivated PARP1 and PAR were exposed to each of two distinct PARP inhibitors, the cell lines initiated a process that resulted in the death of the cells. When mice xenografted with human NSCLC cell lines were given a PARP inhibitor, the treatment significantly slowed tumor growth.
As the group wrote in its report for the American Association for Cancer Research (AACR) journal Cancer Research, the elevated PAR levels predicted the response to PARP inhibitors in vitro and in vivo more accurately than did PARP1 expression itself. This suggests that PAR may be an effective biomarker of response to cisplatin, pointed out Kroemer in an accompanying statement issued by the AACR.
“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,” summarized Kroemer in the AACR statement. “This has clear implications for new treatment regimens and for developing biomarkers of response to cisplatin.”