CRISPR catches out critical cancer changes
Researchers reveal which gene fusions are critical for the growth of cancer cells and identify a new drug target for multiple cancers
In the first large-scale analysis of cancer gene fusions, which result from the merging of two previously separate genes, researchers at the Wellcome Sanger Institute, EMBL-EBI, Open Targets, GSK and their collaborators have used CRISPR to uncover which gene fusions are critical for the growth of cancer cells. The team also identified a new gene fusion that presents a novel drug target for multiple cancers, including brain and ovarian cancers.
The results, published today (16 May) in Nature Communications, give more certainty for the use of specific gene fusions to diagnose and guide the treatment of patients. Researchers suggest existing drugs could be repurposed to treat some people with pancreatic, breast and lung cancers, based on the gene fusions found in their tumours.
Gene fusions, caused by the abnormal joining of two otherwise different genes, play an important role in the development of cancer. They are currently used as diagnostic tools* to predict how particular cancer patients will respond to drugs, as well as prognostics, to estimate the outcome for a patient given the best possible care. They are also the targets of some of the latest targeted treatments for cancer.
Researchers have identified around 20,000** gene fusions so far, however their exact function and role in developing cancer remains poorly understood. Discriminating between fusions that have a role in cancer survival and those that do not has important clinical implications.
In the first large-scale study of gene fusion function, researchers at the Wellcome Sanger Institute, EMBL-EBI, Open Targets, GSK and their collaborators analysed more than 8,000 gene fusions in over 1,000 human cancer cell lines, from 43 different cancer types, including paediatric cancers and cancers with unmet clinical need.
The team tested the cell lines against more than 350 anti-cancer drugs to see which existing drugs could be repurposed to potentially treat cancer patients with gene fusions, and employed CRISPR as a tool to discover which key gene fusions are critical for cancer cell survival.
The team found that 90 per cent of gene fusions do not play an essential role in cancer. These results should be considered when inferring causes of cancer from the genome sequence of patients’ tumours.
“The majority of gene fusions are not essential for the survival of cancer cells. As genome sequencing patients’ tumours becomes more common, those interpreting the data must be careful when considering whether a particular gene fusion is driving the cancer.”
Dr Gabriele Picco Co-first author from the Wellcome Sanger Institute
Researchers also discovered a new fusion, YAP1-MAML2, which is essential for the progression of multiple cancer types, such as brain and ovarian cancers.
“We discovered a handful of gene fusions that are key for cancer survival. These genetic changes may present opportunities for treating patients with existing drugs, or could be the drug targets of the future. We discovered a new gene fusion, YAP1-MAML2, which offers a new drug target for several cancers, including ovarian cancer.”
Dr Mathew Garnett Lead author from the Wellcome Sanger Institute and Open Targets
The results also suggest that gene fusions involving RAF1, ROS1 and BRD4 could be targeted by existing drugs, meaning new treatment options may be available for patients with rare sub-types of pancreatic, breast and lung cancers.
“Cancers differ between people and having a genomic view of these differences is increasing our understanding of cancer and opening up treatment options for patients. This study offers further opportunities to employ gene fusions as therapeutic biomarkers and stratify patients onto clinical trials, potentially offering more targeted and effective clinical studies.”
Dr Julio Saez-Rodriguez Previously from EMBL-EBI and Open Targets, and now based at Heidelberg University
The collaboration between researchers at Sanger, EMBL-EBI and GSK, the Open Targets partners, bolster the translation of these research results into new treatments.
This research contributes towards building the Cancer Dependency Map***, a rulebook for the precision treatment of cancer in the future.
*For example, the gene fusion BCR-ABL is a diagnostic marker and drug target for patients with chronic myeloid leukaemia, who can be treated with Imatinib.
***The Cancer Dependency Map at Sanger is a project with four components – drugs, models, genes and analytics – which together contribute to the production of a rulebook for the precision treatment of cancer. https://depmap.sanger.ac.uk/
Mapping the dependencies of cancers is an international effort by the Sanger Institute in the UK and the Broad Institute in the United States. Researchers aim to bridge the translational gap that exists between genomic sequencing and providing precision medicine to the many cancer patients. Genes that are critical to a cancer’s survival represent dependencies: vulnerabilities that might serve as targets for designing new therapies or repurposing existing ones. Mapping these dependencies is essential to making precision cancer medicine a reality.
Gabriele Picco et al. (2019) Functional linkage of gene fusions to cancer cell fitness assessed by pharmacological and CRISPR/Cas9 screening. Nature Communications. DOI: 10.1038/s41467-019-09940-1
This study was supported by Open Targets.
Open Targets is a pioneering public-private collaboration that aims to transform drug discovery by systematically improving the identification and prioritisation of drug targets and improving the success rate for developing new medicines. The consortium is a unique, pre-competitive partnership between companies and not-for-profit research institutes. The partners are GSK, Biogen, Takeda, Celgene, Sanofi, the Wellcome Sanger Institute and the EMBL’s European Bioinformatics Institute (EMBL-EBI). Open Targets combines the skills, knowledge and technologies of its partner organisations, offering a critical mass of expertise that does not exist in any single institution. Large-scale genomic experiments (Sanger Institute) and computational techniques (EMBL-EBI) developed in the public domain are blended with formal pharmaceutical R&D approaches to identify causal links between targets, pathways and diseases. This enables the partners to systematically identify drug targets, and prioritise them for further exploration. Find more at https://www.opentargets.org/ or follow @targetvalidate
The European Bioinformatics Institute (EMBL-EBI) is a global leader in the storage, analysis and dissemination of large biological datasets. We help scientists realise the potential of ‘big data’ by enhancing their ability to exploit complex information to make discoveries that benefit humankind.
We are at the forefront of computational biology research, with work spanning sequence analysis methods, multi-dimensional statistical analysis and data-driven biological discovery, from plant biology to mammalian development and disease.
We are part of EMBL and are located on the Wellcome Genome Campus, one of the world’s largest concentrations of scientific and technical expertise in genomics.
GSK – a science-led global healthcare company with a special purpose: to help people do more, feel better, live longer. We have 3 global businesses that research, develop and manufacture innovative medicines, vaccines and consumer healthcare products. We aim to bring differentiated, high-quality and needed healthcare products to as many people as possible using our scientific and technical know-how.
In 2014 GSK became one of the founding members of Open Targets to systematically improve the identification and prioritisation of drug targets that could lead to safe and effective medicines. For further information please visit www.gsk.com
The Sanger is one of the world’s leading genome and biodata institutes. Through its ability to conduct research at scale, it is able to engage in bold and long-term exploratory projects that are designed to influence and empower science globally. Institute research findings, generated through its own research programmes and through its leading role in international consortia, are being used to develop new diagnostics and treatments for human disease and to understand life on Earth. Find out more at www.sanger.ac.uk or follow @sangerinstitute on Twitter, Facebook, LinkedIn and on our Blog.
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