CRISPR

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 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.

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 $1–2 billion to develop a single drug, but around 90 percent of drugs fail during development. Selecting a good drug target at the beginning of the process can therefore 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 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 15percent of colon and 28percent 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.

Dr Kosuke Yusa, co-lead author previously from the Wellcome Sanger Institute and Open Targets, now based at the Institute of Frontier Life and Medical Sciences, Kyoto University, said: “CRISPR is an incredibly powerful tool that enables us to do science at a scale and with a precision that we couldn’t do five years ago. With CRISPR we have discovered a very exciting opportunity to develop new drugs targeting cancers.”

Dr Francesco Iorio, co-first author from the Wellcome Sanger Institute and Open Targets, said: “To give a new drug the best chance of succeeding in the very final phases of clinical trials, it is crucial to select the best and most promising drug target at the beginning of the drug development process. For the first time, in a data-driven way, we provide guidance at a genome-scale on which new therapeutic targets should be put forward for the development of new anti-cancer drugs.”

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.