RAS: a moving target

Ras oncogene means different things to different tumours in different tissues. Step away from RAS itself and we enter a universe of complex and diverse biological processes that Ras oncogene orchestrates. In my view, deep understanding of these processes is essential for the development of effective approaches to target Ras oncogene-driven tumours.

Oncogenic RAS itself and oncogenic RAS signalling have been the focus of much research activity for many years, and while they both work in close partnership to drive tumour growth, the considerations that go into how to target them are very different. The unremarkable shape of the RAS protein, which lacks unique target sites for binding small molecules, is still a significant challenge. A major advance in this area has been achieved recently with the development of a new class of covalent inhibitors that irreversibly target the cysteine residue of mutant KRAS G12C. These inhibitors are currently being tested clinically in patients with KRASG12C-positive advanced non-small-cell lung cancer. Updated trial results are expected at the Congress (Abstract 446PD) but, while promising, further exploration into the mode of action of these inhibitors in human tumours is necessary to evaluate their therapeutic potential.

In terms of RAS signalling, the main targeting strategy has relied on the development of specific inhibitors of Ras effectors. The design of such inhibitors has been facilitated by the fact that many of these effectors are druggable protein kinases (e.g. RAF, PI3K). However, given the multiplicity of Ras effectors and the diverse downstream pathways that they control, it is becoming clear that to harness this strategy effectively will depend on establishing context-specific platforms for the combinatorial targeting of Ras effector pathways.

Another approach for targeting RAS, albeit indirectly, takes advantage of our increasing appreciation of the essential role that RAS plays in regulating processes that enhance tumour cell fitness. Among these, metabolic reprogramming and immune evasion have attracted much interest. Recent work suggests that unique pathways of nutrient delivery and utilisation by RAS tumour cells might make them susceptible to existing and novel therapies. The influence of Ras on the immune environment is being recognised as another potentially promising arena. Understanding the immune evasion tactics of RAS could lead to immune-based treatments specific for mutant RAS tumours. There may be unique immune signatures associated with mutant RAS tumours that can be exploited to design immunotherapy approaches that are specifically tailored for these tumours.

As in the past, the future of RAS research holds many surprises and promises to take us into areas that we cannot even foresee.

Today’s keynote lecture is on ‘RAS signalling and cancer’ (12.00 – 12.45, Madrid Auditorium [Hall 2]).


ESMO Congress 2019 abstract:

446PD – Phase I study of AMG 510, a novel molecule targeting KRAS G12C mutant solid tumours