The research, reported today in the Journal Science Signalling, provides new insight into a protein pathway that normally controls cell division – the BRAF-MEK-ERK pathway which is frequently defective in cancer – and greater understanding of tumour cells’ versatility to overcome therapies targeting this pathway.
A growing problem in treating tumours is their ability to develop resistance to new chemotherapeutic drugs, which causes disease relapse. These findings suggest that treatment with AZD6244 in combination with other inhibitors of the pathway may be more successful. This research therefore has important implications for more efficient use of the new generation of drugs that are being developed or are currently undergoing clinical evaluation.
Dr Simon Cook, leading the research at the Babraham Institute, which receives strategic funding from the Biotechnology and Biological Sciences Research Council (BBSRC) said, “We study the basic biology of the RAF-MEK-ERK pathway, how it is regulated and how it controls cell division and cell survival. However, we are also keen to see our research translated into real benefits for health and wellbeing. Our longstanding collaboration with AstraZeneca, investigating how drug resistance arises, is a good example of academic-commercial collaborations delivering discoveries from basic bioscience research to healthcare.”
Cells in our bodies communicate with each other and respond to external stimuli by activating an array of intracellular signalling pathways. For example, a cascade of enzymes called the ERK pathway plays a central role relaying signals from growth factors, which stimulate cell division; faults in this pathway are often associated with the aberrant cell growth seen in cancer. Growth factors turn on a ‘switch’ protein called KRAS, which activates a three-tier cascade of protein kinases called BRAF, MEK and ERK. Active ERK can then phosphorylate an array of proteins in the cell and promote cell division.
Certain human cancers including melanoma, colon, lung, pancreatic and thyroid cancer, have a high incidence of mutations in the KRAS or BRAF genes, which are consequently known as oncogenes – cancer causing genes. The faulty KRAS and BRAF proteins become locked in the ‘on’ state, over-riding cell growth controls, even in the absence of growth factors. This particular pathway has therefore been under the spotlight in the search for new therapeutic strategies, since drugs that inhibit various parts of this pathway could hold promise as new anti-cancer therapies. One candidate drug, AZD6244 (also called Selumetinib), is currently in phase II clinical trials. It effectively acts as a ‘roadblock’, inhibiting the MEK enzyme and disrupting signal transmission down the ERK pathway.
To explore the biology behind this phenomenon, the Babraham team produced derivatives of human cancer cell lines that had acquired up to 100-fold resistance to MEK inhibition. They showed that resistance arises through a common mechanism whereby the faulty ‘oncoprotein’ (KRAS or BRAF) is overproduced by cells to increase the amount of activated MEK, thereby overcoming the block imposed by AZD6244. For cells with BRAF mutations, a combined treatment with both a MEK inhibitor and a RAF inhibitor overcame the resistance.
“The impact of virtually all anti-cancer drugs to date has been marred by the fact that drug-sensitive tumour cells can adapt and become resistant to the drug; essentially they find a way to circumvent the ‘roadblock’ created by the drug,” explained Dr Cook. “Our knowledge of the ERK pathway meant we were able to anticipate the drug resistance as a problem and identify the mechanism at a very early stage. This may influence future treatment strategies by identifying drug combinations which may be more effective in the first instance and which delay the onset of resistance,”
The study of abnormal cells can also lead to new insights into more basic biology. “We see time and again that studying diseased cells actually provides insights into the controls operating in normal cells and this is no exception. Other labs are using similar MEK inhibitors to maintain stem cells in the laboratory. Based on our results it will interesting to see if stem cells are as adaptable as tumour cells and whether similar changes in the RAF-MEK-ERK pathway are seen,” added Dr Cook.
The Babraham Institute is a centre for studying the basic biology of signalling inside and between cells, supporting BBSRC’s mission to drive advances in fundamental bioscience for better health and improved quality of life. It also seeks to translate its work through collaborations with industry and charities to maximize social and economic impact. Institute Director, Professor Michael Wakelam commented, “This is an excellent example of how the quality of research at Babraham has attracted significant financial support from industry to investigate the biology behind a serious concern for the pharmaceutical industry and patient wellbeing – the development of resistance to anti-cancer therapies.”
Notes to editors
Publication details: Amplification of the driving oncogene, KRAS or BRAF, underpins acquired resistance to MEK1/2 inhibitors in colorectal cancer cells. Annette S. Little, Kathryn Balmanno, Matthew J. Sale, Scott Newman, Jonathan R. Dry, Mark Hampson, Paul A. W. Edwards, Paul D. Smith & Simon J. Cook.
About the Babraham Institute
The Babraham Institute is an institute supported by the Biotechnology and Biological Sciences Research Council (BBSRC) near Cambridge, undertaking international quality research to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. The Institute’s research is focused on understanding the biological events that underlie the normal functions of cells and the implication of failure or abnormalities in these processes. Research focuses on signalling and genome regulation, particularly the interplay between the two and how epigenetic signals can influence important physiological adaptations during the lifespan of an organism. By determining how the body reacts to dietary and environmental stimuli and manages microbial and viral interactions, we aim to improve wellbeing and healthier ageing. For more information visit: www.babraham.ac.uk.
AstraZeneca is a global, innovation-driven biopharmaceutical business with a primary focus on the discovery, development and commercialisation of prescription medicines for gastrointestinal, cardiovascular, neuroscience, respiratory and inflammation, oncology and infectious disease.
BBSRC is the UK funding agency for research in the life sciences. Sponsored by Government, BBSRC annually invests around £470M in a wide range of research that makes a significant contribution to the quality of life in the UK and beyond and supports a number of important industrial stakeholders, including the agriculture, food, chemical, healthcare and pharmaceutical sectors.
BBSRC provides institute strategic research grants to the following:
- The Babraham Institute
- Institute for Animal Health
- Institute for Biological, Environmental and Rural Studies (Aberystwyth University)
- Institute of Food Research
- John Innes Centre
- The Genome Analysis Centre
- The Roslin Institute (University of Edinburgh)
- Rothamsted Research
The Institutes conduct long-term, mission-oriented research using specialist facilities. They have strong interactions with industry, Government departments and other end-users of their research.
Dr Claire Cockcroft, Head of External Relations, Babraham Institute
tel: 01223 496260
mob: 07786 335978
Dr Simon Cook, Head of Signalling & Cell Fate Laboratory
tel: 01223 496453
Mike Davies, Media Officer
tel: 01793 414694
fax: 01793 413382
Nancy Mendoza, Senior Media Officer
tel: 01793 413355
fax: 01793 413382
Matt Goode, Head of Corporate Communications
tel: 01793 413299
fax: 01793 413382