23/01/2023
Key points:
Researchers from the Babraham Institute, together with The Institute of Cancer Research (ICR) and University of Dundee, have published their research characterising the disruption to cells caused by HSP90 inhibitors. Heat Shock Protein 90 (HSP90) is important for the stabilisation or activation of around 300 proteins in the cell, many of which are known to be oncogenic. Due to this widespread dependence, inhibitors of HSP90 have been explored as anti-cancer drugs. However, several drug candidates entering clinical trials have led to underwhelming results due to a lack of understanding about the full impact of HSP90 inhibition on the cell’s proteins. The research from the Samant lab at the Babraham Institute, Professor Paul Workman’s group at the Institute of Cancer Research (ICR), and Professor Angus Lamond’s group at Centre for Gene Regulation & Expression, University of Dundee, uses a different approach to provide a more complete picture of the effects of HSP90 inhibition. In addition to informing current drug development on HSP90 inhibitors, their methods of investigation can also be applied to other diseases and chronic conditions where protein interactions are similarly disrupted.
“As HSP90 inhibitors begin to enter clinical use for cancer patients and attract further interest as promoters of healthier ageing, it is important that we have a concrete understanding of how these inhibitors affect the whole repertoire of proteins HSP90 interacts with or influences. Looking at cancer cells soon after treatment, we identified changes to proteins and protein structures involved in core cell structures and functions like protein folding, mitochondria, and the cytoskeleton, that might otherwise have remained hidden with more conventional approaches.” explained Dr Rahul Samant, who began this work as a PhD student with Professor Workman at the ICR before his lab at the Babraham Institute and Bioinformatics facility members undertook further analysis.
HSP90 is a molecular chaperone that helps stabilise a specific but diverse set of proteins, and also maintains multi-protein assemblies, or ‘complexes’. In numerous cancers, HSP90 is thought to act as a driver of disease progression and contribute to drug resistance. This activity makes HSP90 a good target for treatments, but the downside is that it can be hard to predict the consequences when it is inhibited. Studies so far have struggled to combine looking at the changes to protein complexes as well as total abundance.
Dr Samant and Prof. Workman began a collaboration with Prof. Angus Lamond and his postdoc Dr Mark Larance (now a Senior Lecturer at The University of Sydney, Australia) in Dundee, taking advantage of a method that couples the sorting of protein complexes with mass spectrometry, which overcomes some restrictions of previous studies. This multi-dimensional proteomic approach allowed them to identify changes to the proteome that occur in colon cancer cells shortly after treatment with a HSP90 inhibitor. The research produced a resource of 4,645 proteins in cells with or without HSP90 inhibition, uncovering several novel HSP90-dependent proteins.
“First and foremost, we were surprised to find that HSP90 inhibition induced limited changes to protein complexes in the colon cancer cells we tested. The reason for our surprise was HSP90’s central role in maintaining cancer-related protein signals through such complexes.” Dr Samant added “Despite this, we were excited to find several new affected proteins, some of which could begin to explain some of the side effects of HSP90 inhibitors observed in patients.”
The researchers were able to see that an important mitochondrial protein complex used for energy production in healthy cells, but thought to be less important in cancer cells, was disrupted by HSP90 inhibition. This connection had been missed in the past with more conventional methods, but importantly could potentially explain some of the side-effects seen with HSP90 inhibition in the healthy cells of cancer patients. The data from this study, which is available as a resource for exploration through the Institute’s Bioinformatics Facility database, provides a new catalogue of candidate proteins and protein complexes to test in various cell models, to see if they help or hinder the survival of both diseased and healthy cells.
In addition to relevance for cancer treatments, inhibiting HSP90 has the potential to promote healthier ageing by moderating cell senescence (when cells no longer divide as they become aged but contribute to ageing-associated frailty), or by selectively eradicating the senescent cells that do arise. With a more robust picture, and methods that can adequately capture the changes, the team is hopeful that their results will help direct future studies in this area. For example, Dr Samant’s lab is currently using similar multi-dimensional proteomics methods to investigate how protein recycling networks are disrupted across a range of senescent and aged cell models.
More broadly, disruption of global protein assemblies is a common feature of ageing and chronic diseases. Similar studies taking a multi-dimensional proteomics approach to investigate different healthy, aged, and pathologic contexts should provide a more rounded view of how this disruption contributes to ageing and frailty.
Publication reference Samant RS, et al. Native size exclusion chromatography-based mass spectrometry (SEC-MS) reveals new components of the early Heat Shock Protein 90 inhibition response among limited global changes. Mol Cell Proteomics. 2022 Dec 19:100485. doi: 10.1016/j.mcpro.2022.100485
Press contact Honor Pollard, Communications Officer, honor.pollard@babraham.ac.uk
Image description: Composite image of data from the paper and protein structure.
Institute affiliated authors (in author order): Rahul Samant, Group leader, Signalling research programme Estelle Wu, Research Assistant, Samant lab Laura Biggins, Core bioinformatician, Bioinformatics facility Simon Andrews, Head of Bioinformatics Harvey Johnston, Postdoctoral researcher, Samant lab
Research funding This research was supported by funding from Cancer Research UK and the Biotechnology and Biological Sciences Research Council.
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.
About BBSRC 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.
23 January 2023