The rapidly growing landscape of RAS inhibitors: from selective allele blockade to broad inhibition strategies

Abstract

RAS oncoproteins have been considered undruggable for decades. However, recent advances have led to the development of a large variety of RAS inhibitors. While a multitude of drugs is currently under clinical evaluation, some of them have already been approved in specific contexts, leading to a continuous improvement of available therapeutic options for patients with RAS-mutant cancers. In this Viewpoint, we discuss different classes of RAS inhibitors, with emphasis on those that are currently tested in the clinic including allele-specific KRAS, panKRAS, and panRAS inhibitors. We also address determinants of response to RAS inhibition such as the tumor context or potential resistance mechanisms. Finally, we provide an outlook on the future of RAS targeting, which is likely to involve combination therapies. The rapid approval of several RAS inhibitors reflects the urgency to develop novel therapeutic strategies to treat RAS-mutant cancers.

Keywords: KRAS; RAS inhibitors; combination therapies; drug resistance.