Scientists at the Babraham Institute, working with collaborators at AstraZeneca and the MRC Cancer Cell Unit in Cambridge, have discovered how tumour cells acquire resistance to a new anti-cancer drug (AZD6244). 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 health and well-being.”
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 laboratories 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.”
Little AS, Balmanno K, Sale MJ, Newman S, Dry JR, Hampson M, Edwards PAW, Smith PD, Cook SJ (2011) Amplification of the driving oncogene, KRAS or BRAF, underpins acquired resistance to MEK1/2 inhibitors in colorectal cancer cells. Science Signaling 4 ra17 http://dx.doi.org/10.1126/scisignal.2001752
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About the Babraham Institute:
The Babraham Institute undertakes world-class life sciences research to generate new knowledge of biological mechanisms underpinning ageing, development and the maintenance of health. Our research focuses on cellular signalling, gene regulation and the impact of epigenetic regulation at different stages of life. By determining how the body reacts to dietary and environmental stimuli and manages microbial and viral interactions, we aim to improve wellbeing and support healthier ageing. The Institute is strategically funded by the Biotechnology and Biological Sciences Research Council (BBSRC), part of UK Research and Innovation, through an Institute Core Capability Grant and also receives funding from other UK research councils, charitable foundations, the EU and medical charities.
The Biotechnology and Biological Sciences Research Council (BBSRC) is the UK funding agency for research in the life sciences. Sponsored by Government, BBSRC annually invests around £450 million in a wide range of research that makes a significant contribution to the quality of life for UK citizens and supports a number of important industrial stakeholders including the agriculture, food, chemical, health and well-being and pharmaceutical sectors. BBSRC carries out its mission by funding internationally competitive research, providing training in the biosciences, fostering opportunities for knowledge transfer and innovation and promoting interaction with the public and other stakeholders on issues of scientific interest in universities, centres and institutes.
Babraham Bioscience Technologies Ltd is responsible for managing the Babraham Research Campus’ Bioincubator. BBT brings together all the elements to support innovation and enable the successful exploitation of research in the biomedical sector based on technologies emanating from the Babraham Institute and bioventures relocating to the campus. BBT has taken a prominent role regionally, initiating and leading partnerships to promote knowledge and skills flow and has established a reputation for successfully translating innovative science into viable business opportunities through partnerships for wealth creation.
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.
28 March 2011