Publication highlights

The RAS oncogene is mutated in around one in five cancers, and was once referred to as 'undruggable'. Scientists are now focusing on a particular enzyme RAS targets, called PI3K, hoping to stop uncontrolled cancer growth while maintaining the function of RAS in healthy cells. Researchers at the Crick and Vividion Therapeutics used chemical screening to find a series of small compounds thatmight stop the RAS-PI3K interaction without blocking PI3K's other functions. These compounds were then tested in mice with RAS-mutated lung tumours. The treatment effectively halted tumour growth, with no evidence of hyperglycaemia, which is a problem for current drugs on the market. It also slowed tumour growth in mice with HER2 mutations.

Researchers from the Francis Crick Institute, UCL, Gustave Roussy and Memorial Sloan Kettering Cancer Center (MSK), have discovered that expansion of mutant blood cells, a phenomenon linked to ageing, can be found in cancerous tumours, and this is associated with worse outcomes for patients. Clonal haematopoiesis of indeterminate potential (CHIP) is a condition where blood stem cells accumulate mutations over time. The researchers found that tumour-infiltrating clonal haematopoiesis, not CHIP alone, was associated with greater risk of relapse and cancer death. Patients with TI-CH had an expansion of myeloid cells which can support tumour progression and support. They also discovered that blood cells with TET2 mutations were more likely to be tumour-infiltrating, and that TET2 mutant myeloid cells remodelled the tumour microenvironment. Finally, they validated their findings in over 49,000 patients, finding that mutations were more common in harder-to-treat cancer types.

Researchers at the Francis Crick Institute, working with the Amsterdam University Medical Centre, have found that immune cells are held back from fighting lung tumours by another type of cell in the surrounding cellular neighbourhood. The researchers saw that clusters of fighter cells called T cells were gathered near tumours in mice with cancer-causing mutations, but the cell community also contained regulatory T cells (Tregs), which were stopping immune cell coordination. When the researchers blocked the action of Tregs, the mice responded better to a KRAS inhibitor, a type of cancer drug, showing reduced tumour growth and longer survival.

The Oncogene Biology Laboratory at the Crick, in collaboration with Revolution Medicines, have tested a combination of treatments in mice with lung cancer and shown that these allow immunotherapies to target non-responsive tumours. They combined a newly identified KRAS G12C inhibitor, a compound that blocks a protein called SHP2 (which inhibits cancer cells and can also activate tumor immunity), and an immune checkpoint inhibitor (which blocks proteins that helps the cancer cells hide from the immune system). In mice with functional immune systems, the triplet combination shrank the tumours and, in some mice, fully eradicated them. Even in mice with ‘immune cold’ tumours that are normally unresponsive to immunotherapy, the combination allowed tumours to become sensitised to the immune checkpoint inhibitors.

Researchers at the Francis Crick Institute, UCL and AstraZeneca have discovered the reason why targeted treatment for non-small cell lung cancer fails to work for some patients, particularly those who have never smoked. The study shows that lung cancer cells with two particular genetic mutations are more likely to double their genome, which helps them to withstand treatment and develop resistance to it. The researchers re-analysed data from the trials of a new EGFR inhibitor, which blocks a common genetic mutation in this type of lung cancer. They compared the impact of treatment for patients with either EGFR-only or with EGFR and p53 mutations, finding that tumours got smaller in response to treatment for patients with just EGFR mutations. But for patients with both mutations, some tumours had grown, providing evidence of rapid drug resistance. This was confirmed in mice with both mutations - resistant cells had doubled their genomes.

Enzymes called ZDHHCs are responsible for directing a type of regulatory modification, palmitoylation, that adds a lipid to specific proteins, but humans have 23 different ZDHHCs, and understanding which proteins each one modifies has been very challenging. A team led by satellite group leader Ed Tate have developed a new method that identifies the set of proteins just one ZDHHC acts on, which has ramifications not just for our understanding of lipid biology, but also for therapeutic strategies targeting proteins whose activity depends on palmitoylation. To progress the research into drug discovery, the researchers have also screened a very large library of compounds to find effective ZDHHC inhibitors.

Researchers in the Downward lab have studied the effects of combining immune checkpoint blockade with KRAS inhibitors, in mice. In tumours where there were already high numbers of active immune cells, so called ‘immune hot’ tumours, the treatment successfully controlled the cancer. However, in cases where the immune system was not able to mount a strong response, the combination treatment was ineffective.