Double strike against cancer
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Double strike against cancer

13.06.2013 - German researchers have found a way to circumvent chemotherapy resistance in cancer cells.

A new therapeutic approach can take advantage of cancer cells' need to repair double-strand breaks in DNA, in order to overcome the tumour's resistance to chemotherapy (Science Transl. Medicine). According to the research group headed by Hans Christian from University Cologne, mutations in the ATM gene protect cancer cells from cell death during chemotherapy. ATM  is instrumental in initiating DNA repair and inducing cell death when repair is not possible in curse of the so-called DNA damage response (DDR).  

But now the researchers have found that the protection offered by ATM mutations comes at a cost – dependence on a DNA-repairing enzyme called DNA-PKcs (DNAdependent protein kinase catalytic subunit). In experiments with mouse and human cancer cells, Christian et al. proved that it's possible to exploit this weak spot to fight blood cancer and solid tumours. Treating the cells with drugs that block DNA-PKcs led to cancer cell death. Intriguingly, both healthy cells and cancer cells with normal ATM function can tolerate the loss of DNA-PKcs, suggesting few side effects. The findings hint that drugs designed to specifically kill ATM-deficient tumours could benefit cancer patients.   The dependence of ATM-defective cells on DNA-PKcs offers a window of opportunity for therapeutic intervention: Either pharmacological or genetic abrogation of DNAPKcs in ATM-defective cells led to the accumulation of DNA double-strand breaks and the subsequent CtBP-interactingprotein (CtIP)-dependent generation of large single-stranded DNA (ssDNA) repair intermediates. These ssDNA structures trigger proapoptotic signalling through the RPA/ATRIP/ATR/Chk1/p53/Puma axis, ultimately leading to the apoptotic demise of ATM-defective cells exposed to DNA-PKcs inhibitors such as Celgene Corp.'s compound CC115. According to the researchers, such DNA-PKcs inhibitors are effective as single agents against ATM-defective lymphomas in vivo. CC-115 binds to and inhibits the activity of DNA-PK (DNA-dependent protein kinase) and both raptor-mTOR (TOR complex 1 or TORC1) and rictor-mTOR (TOR complex 2 or TORC2), which may lead to a reduction in cellular proliferation of cancer cells expressing DNA-PK and TOR.  

Christian told EuroBiotechNews that his group currently is in negotiation with Celgene which is currently in Phase I testing of CC115. "We would like to extend the trial to a ATM-stratified population of CCL patients," he said. ATM is overexpressed in 10% of blood cancers and 10% of carcinomas of the lungs, colon, and pancreas.



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