Gene fusions point to radiation resistance in prostate cancer

Ann Arbor, MI-Results of in vitro studies indicate that E-twenty six (ETS) gene fusions in prostate cancer may be a biomarker of radiation resistance and a potential target for reversing radioresistance through treatment with a poly(ADP-ribose)polymerase 1 (PARP1) inhibitor, according to researchers from the University of Michigan, Ann Arbor.

"We are very excited by our findings, considering there are several PARP inhibitors that are already being investigated in phase II and III clinical trials, and so hopefully one might become commercially available in the not-too-distant future," said first author Felix Feng, MD, assistant professor of radiation oncology at the University of Michigan. "Now, we are in the process of planning a clinical trial to investigate the efficacy and safety of PARP inhibition using one of these investigational agents for reversing radiation resistance of prostate cancer."

ETS gene fusions, which consist of the fusion between an androgen-sensitive promoter and a transcription factor, are considered to be driving mutations in about half of all prostate cancers. ETS Related Gene (ERG) is the prototype transcription factor in ETS gene fusions, and through their interest in investigating associations of ETS gene fusions in prostate cancer, Dr. Feng and colleagues recently discovered that ERG, as well as other ETS transcription factors, interact with PARP1 (Cancer Cell 2011; 17:664-78).

Assays performed after radiation exposure showed that relative to controls, prostate cancer cells overexpressing ERG had increased efficiency of DNA repair and increased survival, both of which were reversed when radiation exposure was performed after addition of a PARP1 inhibitor to the cell cultures. The benefit of PARP1 inhibition was seen using different investigational PARP1 inhibitors as well as in PARP1 knockout cells, the researchers reported at the 2011 American Society of Clinical Oncology annual meeting in Chicago.