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Cambridge team discovers novel pathway involved in therapy-resistant cancers

Scientists at The Babraham Institute have begun to unpick the complex mechanisms underpinning the development of drug resistant cancers. They have identified a novel target that may help to combat the growing problem of therapy resistant cancers and pave the way for innovative therapeutic approaches.

Their discovery, reported in the latest edition of the New England Journal of Medicine, centres on the significance of DNA damage for both normal cells and cancer cells. It reveals that a biochemical signalling pathway, that normally ensures damaged cells are diverted towards cellular suicide, is blocked in certain cancers, rendering them resistant to certain types of treatment.

DNA damage is a common event in a cell’s life, a consequence of incorrect copying of the DNA during cell division or provoked by elements in our environment like tobacco smoke and sunlight. However, if DNA damage occurs, the cell normally triggers a repair response and if the damage is not repaired, the cell is targeted for cell death, a process known as apoptosis. In this way the body protects itself from cells that might become cancerous. The cells that do become cancerous manage to by-pass these repair and self-destruction pathways, promoting the survival of damaged cells.

The research is a collaboration between the BBSRC-funded Babraham Institute, the University of Cambridge and Addenbrooke’s Hospital, using cells from patients with chronic myeloid leukaemia (CML), and polycythemia vera (PV), two myeloproliferative disorders.

Cancers, such as the leukaemias investigated in this work, are characterised by an accumulation of DNA damage. DNA damage triggers several pathways to ensure that cells die by apoptosis. The authors describe a key new pathway involved in this process, and its subversion in cancer cells.

The team have found that DNA damage in normal cells increases the activity of a proton pump located in the cell membrane, known as NHE-1, which raises the pH of the cell. This has a critical effect on a protein called Bcl-xL, known as a survival protein because of its ability to suppress cell death. However, in the more alkaline environment (higher pH) a chemical process called deamidation converts Bcl-xL into a form that allows cells with damaged DNA to die. The authors have discovered that this pathway is inhibited in (cancerous) myeloid cells, keeping them alive to proceed with their deadly mission. This is the first demonstration of a role for deamidation in human malignancy.

Both the leukaemias studied by the authors are caused by oncogenic tyrosine kinases. These are enzymes - chemical catalysts - that trigger cancer when their activity is abnormally high. These kinases not only cause cells to become cancerous in the first place, but also make the cells resistant to chemotherapy and radiotherapy once they have turned into cancer cells. The authors have discovered that it is these kinases that block the key Bcl-xL deamidation pathway that normally allows DNA damaged cells to die. The activated tyrosine kinase causing CML is called BCR-ABL, whereas in PV the culprit is JAK-2. Altogether more than 30 aberrant tyrosine kinases are known to cause human cancers.

“This discovery provides new insights into how oncogenes, the genes that cause cancer, allow cells to accumulate more and more damage to their DNA without dying”, explains Dr Denis Alexander. “This new understanding of how oncogenes work also opens up some interesting ideas for future cancer therapies".

Cancer therapies depend to a large degree on the DNA damage caused by chemotherapy or radiotherapy, causing cancer cells to die. However, in cancers caused by tyrosine kinases the cells are often resistant to such therapies, referred to as ‘genotoxic resistance’. Fortunately inhibitors of the oncogenic kinases are now being increasingly used in the clinic but the kinases sometimes mutate so that this therapy no longer works.

The therapeutic interest in this research comes from the authors’ finding that simply switching back on the Bcl-xL deamidation pathway causes the cancer cells to die. This can be engineered in living cells by increasing the pH inside the cells artificially, which causes the Bcl-xL to deamidate so that the cells undergo apoptosis.

This therapeutic ‘proof-of-principle’ was dramatically illustrated by studying a CML patient’s cells which had become resistant to Imatinib, the BCR-ABL inhibitor now widely used in the clinic. As expected, Imatinib was unable to restore the Bcl-xL deamidation pathway in the patient’s cells. But the resistance could be bypassed by artificially (genetically) increasing the level of NHE-1 in the drug-resistant CML cells when studied in the laboratory, so increasing cancer cell death. So drug resistance can be overcome by activating the NHE-1 pathway, thereby increasing the pH inside the cell, and in turn Bcl-xL deamidation and apoptosis.

The discovery that modulating the NHE-1/Bcl-xL signalling pathway can override resistance to controlled cell death (apoptosis) in cancers like CML and PV, paves the way for new therapeutic approaches that could be of immense importance in cancers where Bcl-xL plays a pivotal role in genotoxic resistance.

This research was supported by the Association for International Cancer Research, the Biotechnology and Biological Sciences Research Council (BBSRC), the U.K. Leukaemia Research Fund, the Wellcome Trust, the U.K. Medical Research Council, Cancer Research UK, and the U.S. Leukemia and Lymphoma Society.

Dr Denis Alexander | alfa
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