The current state of the art and future trends in RAS-targeted cancer therapies

Abstract

Despite being the most frequently altered oncogenic protein in solid tumours, KRAS has historically been considered 'undruggable' owing to a lack of pharmacologically targetable pockets within the mutant isoforms. However, improvements in drug design have culminated in the development of inhibitors that are selective for mutant KRAS in its active or inactive state. Some of these inhibitors have proven efficacy in patients with KRAS^G12C-mutant cancers and have become practice changing. The excitement associated with these advances has been tempered by drug resistance, which limits the depth and/or duration of responses to these agents. Improvements in our understanding of RAS signalling in cancer cells and in the tumour microenvironment suggest the potential for several novel combination therapies, which are now being explored in clinical trials. Herein, we provide an overview of the RAS pathway and review the development and current status of therapeutic strategies for targeting oncogenic RAS, as well as their potential to improve outcomes in patients with RAS-mutant malignancies. We then discuss challenges presented by resistance mechanisms and strategies by which they could potentially be overcome.

Fig. 1. The RAS signalling pathway and therapeutic approaches to target this pathway in cancer.

Numerous direct inhibitors have been developed to target mutant RAS proteins, either in their inactive, GDP-bound state (‘KRAS-off inhibitors’) or in their active, GTP-bound state (‘RAS-on inhibitors’). Many of these inhibitors are being evaluated in clinical trials. The RAS signalling pathway has many upstream and downstream mediators, which are attractive targets for combination therapies with RAS inhibitors to improve antitumour responses and to mitigate intrinsic and acquired resistance; agents that have been combined with direct KRAS inhibitors in preclinical or clinical studies are listed. Therapeutic cancer vaccines against mutant RAS epitopes and small interfering RNA (siRNA)-based approaches that target oncogenic RAS isoforms are also under ongoing development. ILK, integrin-linked kinase; mTORC2, mTOR complex 2; PI3K, phosphatidylinositol 3-kinase; RTK, receptor tyrosine kinase.

Fig. 2. The prevalence of KRAS, NRAS and HRAS mutations across cancer types.

Mutations in the RAS genes are common in gastrointestinal and lung cancers, with KRAS mutations comprising most of these mutations, but also occur more rarely in various other cancer types. The data shown in the graph are from the cBioportal TCGA and MSK-IMPACT cohorts (available via the cBioPortal for Cancer Genomics)^,.

Fig. 3. The influence of mutant KRAS on the tumour immune microenvironment.

Activating KRAS mutations have numerous implications for the tumour immune microenvironment^,, including activation and recruitment of macrophages, polarization of M1 to M2 macrophages, and suppression of CD8⁺ T cells via effects on MHC–T cell receptor (TCR) and PD-L1–PD-1 signalling as well as via activation of myeloid-derived suppressor cells (MDSCs) and regulatory T (T_reg) cells. Together, these alterations in the tumour microenvironment present opportunities for intervention in the treatment of KRAS-mutated malignancies, and pertinent examples are provided. DC, dendritic cell; ICAM1, intercellular adhesion molecule 1.