Research from Institute scientists has created a new understanding of how cancer cells develop drug resistance. These findings will inform strategies that repress the occurrence of drug resistance and ensure effective treatments for longer, with this knowledge already being applied to prolong the effectiveness of a current cancer treatment. The research is published in the latest issue of NAR Cancer.
In cancer treatment, the development of drug resistance is a frequent problem, and one that drug combinations and treatment regimens are designed to delay for as long as possible. However, drug resistance still limits long-term patient survival.
A key question is whether the resistant cells were present in the original tumour when treatment began, or whether the resistant cells arise during the course of treatment.
Research from the groups of Dr Jon Houseley in the Epigenetics research programme and Dr Simon Cook in the Signalling research programme set out to determine when and how the DNA mutations are formed that lead to cancer drug resistance.
“If the drug resistant cell is present in the original tumour when the treatment starts then the emergence of drug resistance is inevitable,” explains Dr Houseley. “However, if the resistance mutation forms during treatment this opens up the possibility of using an additional drug to prevent the mutation process. We show in the paper that this works.”
With the help of several of the Institute’s science facilities – Bioinformatics, Genomics, Flow Cytometry and Imaging – the researchers used a model colorectal cancer cell system to show that drug resistance arises during treatment as cells attempt to replicate under exposure to the drug.
The researchers started by characterising the gene amplification event that leads to resistance to the MEK inhibitor selumetinib (AZD6244/ARRY-142886). Using several colorectal cell lines they showed that a newly acquired gene amplification (of the BRAF oncogene) was the primary cause of resistance to selumetinib, indicating that resistance arises as a result of the presence of the drug.
Following this, the team assessed the effect of selumetinib on the progression of cells through the cell cycle, the multi-stage process that cells go through to divide. Selumetinib imposes a cell cycle arrest on cells, preventing cell division and initiating cell death. However, despite the presence of the drug, the researchers found that some cells escape this arrest and were able to undergo DNA replication even in the presence of selumetinib.
By exploring the effect of selumetinib on cell cycle progression and analysing the expression of DNA replication and repair genes throughout the cell cycle, the researchers found that cancer cells exposed to the drug but with replicative potential had reduced expression of genes important for error-free DNA replication. This highlighted the potential mechanism for how resistance-conferring mutations developed.
To test this hypothesis, the researchers used a drug combination, applying a drug called palbociclib which inhibits cell cycle progression, to prevent the cancer cells from entering the DNA replication phase at a time when DNA quality control mechanisms are at their least robust. They found that this intervention was effective at delaying the occurrence of resistance, extending the mean time to resistance by three to eight weeks in five drug-resistant cell lines.
Lead researcher, Dr Prasanna Channathodiyil, who undertook this research while a postdoctoral researcher in the Houseley lab, said: “Our findings indicate that resistance to MEK inhibitors, specifically selumetinib in this case, is often acquired through a defined mechanism that can be inhibited. This gives us hope that resistance to cancer drugs can be managed and prevented through our knowledge of how the compromising mutations arise.”
Dr Simon Cook, whose collaborative work with AstraZeneca goes back over 22 years, commented: “This work is another example where our fundamental discovery research provides the basis for important advances in drug development and clinical treatment. Our partnership with the Oncology R&D unit at AstraZeneca means rapid sharing of information between our academic lab and AstraZeneca’s commercial advances for the benefit of cancer patients around the world.”
Channathodiyil, P. et al. (2022) Escape from G1 arrest during acute MEK inhibition drives the acquisition of drug resistance. NAR Cancer
Honor Pollard, Communications Officer, firstname.lastname@example.org
A researcher pipetting cell culture growth media into a plastic culture dish in a sterile flow hood.
Affiliated authors (in author order):
Prasanna Channathodiyil, former postdoc, Houseley lab. Now a senior scientist in Translational Medicine, Oncology R&D, AstraZeneca, Cambridge, UK.Kieron May, PhD student, Houseley lab
Anne Segonds-Pichon, Biological Statistician, Bioinformatics facility
Simon Cook, Institute Director, group leader and Head of the Institute’s Signalling research programmeJon Houseley, group leader, Epigenetics research programme, and Head of KEC
This work was supported by the Wellcome Trust (award 110216) to Prasanna Channathodiyil and Jon Houseley, BBSRC funding to Prasanna Channathodiyil and Jon Houseley, and to Simon Cook, and funding from Cancer Research UK to Simon Cook.
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 Institute Strategic Programme Grants and 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 part of UK Research and Innovation, a non-departmental public body funded by a grant-in-aid from the UK government.
BBSRC invests in world-class bioscience research and training on behalf of the UK public. Our aim is to further scientific knowledge, to promote economic growth, wealth and job creation and to improve quality of life in the UK and beyond.
Funded by government, BBSRC invested £451 million in world-class bioscience in 2019-20. We support research and training in universities and strategically funded institutes. BBSRC research and the people we fund are helping society to meet major challenges, including food security, green energy and healthier, longer lives. Our investments underpin important UK economic sectors, such as farming, food, industrial biotechnology and pharmaceuticals.
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