Cancer drug discovery targeting the interaction of RAS oncogenic proteins with phosphoinositide 3-kinase

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It is estimated by Cancer Research UK that there are 17 million people developing cancer worldwide each year - which sadly causes 9.6 million death annually, making cancer one of the deadliest diseases of our time. Cancer remains a very challenging disease to cure despite the significant research effort that has been made through several decades. This is because cancer is a complex disease that is caused by multiple genetic mutations that occur in important cellular proteins - named oncogenic proteins. Oncogenic proteins are proteins that once mutated become hyperactive and causes several types of cancer. They contribute in the signaling and activation of several cellular pathways that are involved in cellular growth and proliferation. One of the major oncogenic protein families that causes almost 20% of human cancer is the RAS family of proteins. RAS proteins oscillate between two states, ON and OFF. The ON state of RAS interacts with several downstream enzymes to control cellular growth and proliferation. Oncogenic mutations in RAS lock it into the ON state, which causes constant and uncontrolled cellular growth and several types of cancers. Since the discovery of RAS protein in the 1980s, many efforts have been made to find inhibitors against oncogenic RAS. However, RAS proteins are challenging drug targets, despite the development of inhibitors that target one specific RAS mutation, G12C, which only represents 14% of total RAS oncogenic mutations. Therefore, applying new strategies that targets oncogenic-RAS mutants is an urgent requirement. Previous work in the Downward laboratory at the Francis Crick Institute (Crick) has established that blocking the interaction of RAS proteins with a particular downstream target enzyme named p110a inhibits tumour growth driven by RAS oncogenes in mice. Importantly blocking the KRAS/p110a interaction had no toxic effects in normal adult mice. These studies strongly support the idea that the complex of RAS with p110a protein may be an important drug target for future cancer therapies. Although these results are very encouraging, the nature of the weak RAS/p110a interaction makes it difficult to use available screening assays to discovery novel inhibitory chemicals which might be developed into drugs for treating cancers. We therefore initiated a collaboration with the pharmaceutical company AstraZeneca to develop a suitable screening assay for the RAS/p110a interaction. This was successfully achieved, resulting in a joint publication between the Crick and AstraZeneca in 2020. This secondment will strengthen our already successful collaboration with AstraZeneca and enable us to take the project to the next stage. I will apply the newly developed assay system to carry out high throughput screening of libraries of millions of chemical compounds to identify inhibitors that blocks RAS/p110a interaction. By combining expertise from two world class organisations - from academia, the Crick and from the pharmaceutical industry, AstraZeneca - we will maximise the chances of success for the project. Finding inhibitors that blocks the RAS/p110a interaction could lead the way to developing future treatments for all cancers driven by oncogenic RAS mutations, or around 20% of all human cancers.