New Cancer Drug Targets Accelerate Path To Precision Medicine

Researchers discovered thousands of genes essential for cancer’s survival and ranked which ones show the most promise as drug targets for developing new treatments

In one of the largest studies of its kind, researchers used CRISPR technology to disrupt every gene in over 300 cancer models from 30 cancer types and discover thousands of key genes essential for cancer’s survival. The team, from the Wellcome Sanger Institute and Open Targets, then developed a new system to prioritise and rank 600 drug targets that show the most promise for development into treatments.

The results, published today (10 April) in Nature, accelerate the development of targeted cancer treatments and bring researchers one step closer to producing the Cancer Dependency Map, a detailed rulebook of precision cancer treatments to help more patients receive effective therapies.

Every two minutes someone in the UK is diagnosed with cancer, and one in two people will develop cancer at some point in their lives. Surgery, chemotherapy and radiotherapy are commonly used to treat cancer, however while they can be effective at killing the cancer cells, some patients don’t respond to treatment and healthy tissue can be damaged, leading to unwanted toxic side effects for patients.

Scientists and pharmaceutical companies are exploring new targeted therapies that selectively kill cancer cells, leaving healthy tissue unharmed. Currently, producing new effective treatments is very difficult; it costs approximately $1-2B to develop a single drug, but around 90 per cent of drugs fail during development. Therefore, selecting a good drug target at the beginning of the process can be seen as the most important part of drug discovery.

Researchers at the Wellcome Sanger Institute, GSK, EMBL-EBI, Open Targets and their collaborators have conducted one of the largest CRISPR screens of cancer genes to date, disrupting nearly 20,000 genes in over 300 cancer models from 30 cancer types to uncover which genes are critical for cancer survival. The team focused on common cancers, such as lung, colon and breast, and cancers of particular unmet clinical need, such as lung, ovarian and pancreatic, where new treatments are urgently needed.

Scientists identified several thousand key cancer genes and developed a prioritisation system to narrow down the list to approximately 600 genes that showed the most promise for drug development.

A top-scoring target gene present in multiple different cancer types was Werner syndrome RecQ helicase (WRN). The team found that cancer cells with a faulty DNA repair pathway, known as microsatellite unstable cancers, require WRN for survival. Microsatellite instability occurs in many different cancer types, including 15 per cent of colon and 28 per cent of stomach cancers.^* The new identification of WRN as a promising drug target offers an exciting opportunity to develop the first cancer treatments to target WRN.^**

The collaboration between researchers at Sanger, EMBL-EBI and GSK, the Open Targets partners, bolster the translation of these research results into new treatments.

The datasets produced in this new study lay the foundations for producing the Cancer Dependency Map,^*** a detailed rulebook for the precision treatment of cancer.

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.

^*I Cortes-Ciriano et al. (2017) A molecular portrait of microsatellite instability across multiple cancers. Nature Communications. DOI: 10.1038/ncomms15180

^**In a complementary paper also published in Nature, a team led by researchers from the Broad Institute of MIT and Harvard, and the Dana-Farber Cancer Institute in the United States conducting similar dependency mapping experiments also discovered a strong dependency on WRN in microsatellite unstable cancers, lending further support to WRN as a promising drug target. Find out more: https://www.broadinstitute.org/node/495166/

^***The Cancer Dependency Map at the Sanger Institute 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/