Research ArticleCancer

Therapeutic Targeting of a Robust Non-Oncogene Addiction to PRKDC in ATM-Defective Tumors

Science Translational Medicine  12 Jun 2013:
Vol. 5, Issue 189, pp. 189ra78
DOI: 10.1126/scitranslmed.3005814

You are currently viewing the editor's summary.

View Full Text
As a service to the community, AAAS/Science has made this article free with registration.

Two Wrongs Making a Right for Cancer Treatment

When a cell’s DNA is damaged, its normal response is to repair its DNA or undergo apoptosis, a programmed death for cells that are damaged beyond repair. Cancer cells don’t always undergo apoptosis when they should and thus accumulate mutations over time. Even cancer cells, however, need to have some way to repair DNA damage, particularly double-strand breaks, to survive. The two normal mechanisms for such repair are homologous recombination (HR) and nonhomologous end joining (NHEJ). HR requires the function of ATM, a kinase that’s frequently mutated in cancer cells. NHEJ is a more error-prone pathway that does not require ATM but does require another kinase, DNA-PKcs (DNA-dependent protein kinase catalytic subunit).

Now, Riabinska et al. show a way to target ATM-mutant cancer by taking advantage of the cells’ need to repair double-strand breaks in DNA. The inhibition of DNA-PKcs in cancers that were already deficient in ATM proved to be very effective for forcing them to undergo apoptosis because they could no longer repair double-strand breaks in DNA at all. DNA-PKcs inhibition did not kill normal cells or cancer cells that had a functioning HR pathway.

Thus far, the effects of treating ATM-deficient tumors with DNA-PKcs inhibitors have only been shown in cultured cells and in mice, so this approach still needs to be tested in human patients. This may happen soon because one such inhibitor is already in clinical trials. In the meantime, it looks like making things go wrong in two different DNA repair pathways may yet be the right approach for treating some cancers.