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.
- PHYSICAL SCIENCES
- EARTH SCIENCES
- LIFE SCIENCES
- SOCIAL SCIENCES
Subscribe to the newsletter
Stay in touch with the scientific world!
Know Science And Want To Write?
- Science Left Behind: The Anti-Vaccine Update Update
- Moderate Pot Use By Adolescents Doesn't Hurt IQ
- What Americans Fear Most Isn't Ebola Or Terrorism, It's...
- Finding Fracking Fluids In The Environment
- Ashes And Vegetables: The Diet Of Roman Gladiators Was Rather Poor
- Manly Men And Feminine Women Are Not Evolutionary Mandates - They Are Urban Ones
- Dopamine Receptor Agonist Drugs Linked To Gambling And Hypersexuality
- "why are you in all the arguments? Teach me how to get into more arguments. Also, teach me wft to..."
- "So if spirituality is selected for, that has nothing to do with evolution. If that is the case..."
- "said the unscientifically backed atheist to the other atheist..."
- "Obviously, rather than embracing the fact that humans are irrational and admiring the results,..."
- "I find this debate between two relatively learned people humorous. Atenism, whatever it is, died..."
- An end to fat shaming? The 50 year DNA mystery of metabolic dysfunction may soon be solved
- Egg freezing: a smart career move?
- Despite resistance, China will dominate future of GMOs
- Should Science and Nature run advertorial by wacky Dr. Bronner’s that misleads on GMOs?
- Jack the Ripper’s identity remains a mystery after error in DNA analysis revealed
- Seed patent primer: Is the use of GMOs preventing farmers from reusing their seeds?
- Teenage self-harm linked to problems in later life
- Unsteady on your feet? Little touches could make all the difference
- Promising blood biomarkers identified for colorectal cancer: Is a screening blood test within reach?
- Studies must be carried out to determine whether exercise slows the onset of type 1 diabetes in children and adults
- Clot dissolver tPA's tardy twin could aid in stroke recovery