Searching for novel therapeutic approaches to RAS, the commonest and least tractable oncogene

Julian Downward, Cancer Research UK London Research Institute, UK

RAS oncogenes are the most commonly activated in human cancer, with over a million deaths a year caused by cancers driven by mutationally activated RAS. However, despite RAS proteins being exceptionally well-validated cancer targets, little progress has been made in targeting them in the clinic. This is now beginning to change with a number of advances being made recently in the development of protein-protein interaction inhibitors that block RAS interaction with effector enzymes and also renewed approaches to targeting the post-translational processing of RAS.

My laboratory has concentrated on targeting downstream effectors of RAS, such as RAF protein kinases and type I phosphoinositide 3-kinases (PI3Ks). Disruption of the interaction of PI3K p110α with oncogenic mutant KRAS has been shown to prevent tumour development in a mouse model of KRAS driven lung cancer and also to cause partial regression of established tumours. Additional inhibition of the RAF/ERK pathway with MEK inhibitors causes improved tumour regression in these models, but may prove unacceptably toxic.

Another means of targeting this critical oncogene is the identification of unique dependencies of RAS mutant tumour cells through the use of functional genomic screens, or a synthetic lethal approach. We have identified signalling networks that are essential for RAS mutant cells, but not cells with wild type RAS, including a transcriptional programme controlled by the GATA2 transcription factor which involves the proteasome, NF-κB and Rho signalling. Several synthetic KRAS synthetic lethal screens have been carried out, with rather variable results. However, the one constant feature that has emerged across multiple screens is the proteasome, suggesting that it would be worth re-examining proteasome inhibition in KRAS mutant tumours, especially since a large number of new and less toxic proteasome inhibitors are now in late stage clinical development.


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