Dual Targeting Eradicates Cancer Cells
Inhibition of two likely DNA repair mechanisms has been shown to completely eradicate BRCA-deficient tumour cells.
The BRCA genes shot to fame with Angelina Jolie, but despite a lot of people knowing its name, not a lot know what it does. BRCA1 and BRCA2 code for BRCA proteins. These are involved in DNA repair. When a mutation stops them from working properly, mutations build up. This can often lead to cancer. One of the reasons the cancer cells still survive, is because there are still other DNA repair mechanisms the cell can rely on.
“Cancers cells have multiple ways of protecting themselves from death,” explained Tomasz Skorski, MD, PhD, Professor of Microbiology and Immunology and Associate Professor at the Fels Institute for Cancer Research and Molecular Biology at Lewis Katz School of Medicine at Temple University.
Professor Skorksi is a senior investigator on a paper published earlier this week in Cell Reports. The paper describes an approach that effectively combines therapeutic approaches to eliminate some of the cells ‘back up’ plans for DNA repair.
One of the frequent routes for DNA repair in cancerous cells is through PARP1. Inhibiting PARP1 production has been shown to significantly improve progression-free survival in patients with cancers involving hereditary BRCA mutations. By eliminating the cell’s ability to repair its DNA, they die.
Over time, however, the effectiveness of PARP1 inhibition declines, and cancer relapses. According to Professor Skorski, this happens because targeting one pathway is not enough. “The tumour cells eventually escape PARP1 inhibition by activating another backup to the BRCA-mediated repair pathway,” he said. “Our previous work had suggested that RAD52-dependent pathways are a likely escape route, which led us to see whether simultaneous inhibition of both PARP1 and RAD52 could trigger more effective lethality.”
Initial tests involved using an experimental RAD52 inhibitor, in conjunction with a PARP inhibitor (olaparib), on BRCA-deficient solid tumour and leukaemia cell lines in vitro. The approach completely eradicated all BRCA-deficient tumour cells in all types.
The next round of testing observed the results of the same approach in mice. While not quite as effective, the in vivo test still showed that the dual inhibition was significantly more effective than either agent on its own.
It should also be noted that, in both in vitro and in vivo normal cells with unaffected BRCA genes, the dual treatment had no negative effects. “Normal cells continue to use BRCA-mediated repair as their primary DNA repair pathway and do not rely heavily on PARP1 or RAD52,” explained Katherine Sullivan-Reed, a graduate student in Professor Skorski’s research laboratory and first author on the paper.
The research paves the way to develop a drug to inhibit RAD52, and to identify other potential targets. “One of our primary goals is to find additional targets to kill cancer cells, without increasing toxicity,” stated Professor Skorski.