Drugging the Undruggable: Advances on RAS Targeting in Cancer

Abstract

Around 20% of all malignancies harbour activating mutations in RAS isoforms. Despite this, there is a deficiency of RAS-targeting agents licensed for therapeutic use. The picomolar affinity of RAS for GTP, and the lack of suitable pockets for high-affinity small-molecule binding, precluded effective therapies despite decades of research. Recently, characterisation of the biochemical properties of KRAS-G12C along with discovery of its ‘switch-II pocket’ have allowed development of effective mutant-specific inhibitors. Currently seven KRAS-G12C inhibitors are in clinical trials and sotorasib has become the first one to be granted FDA approval. Here, we discuss historical efforts to target RAS directly and approaches to target RAS effector signalling, including combinations that overcome limitations of single-agent targeting. We also review pre-clinical and clinical evidence for the efficacy of KRAS-G12C inhibitor monotherapy followed by an illustration of combination therapies designed to overcome primary resistance and extend durability of response. Finally, we briefly discuss novel approaches to targeting non-G12C mutant isoforms.

Hacking Pancreatic Cancer: Present and Future of Personalized Medicine

“…Despite this, several KRAS-binding small molecules (e.g., Sotorasib, Adagrasib) have been recently developed to irreversibly inhibit the G12C missense mutant of KRAS, showing encouraging results in various cancer types, including non-small cell lung cancer. These agents might thus represent a promising strategy in the small proportion of PC harboring the G12C mutation [ 71 ]. Farnesylation is essential for the membrane anchorage of RAS proteins and the consequent RAS activity.…”

The Importance of Being PI3K in the RAS Signaling Network

“…Recently, several small molecules (AMG510, MRTX849, JNJ-74699157, and LY3499446) have been developed to specifically target K-Ras G12C, culminating with the FDA approval of Sotorasiv (AMG510) [ 401 ]. Further discussion of the different approaches used over the past decades to inhibit oncogenic Ras is provided by a recent review from Molina-Arcas et al [ 402 ].…”

“…Hyperactivation of the PI3K pathway in cancer, and its vital function in cell survival and proliferation, have made it an ideal target for treatment. Furthermore, the inhibition of Ras-effector pathways has for years been considered the most effective approach to target Ras-driven tumors [ 402 , 403 ]. Results from clinical trials with PI3K inhibitors in solid tumors have been, however, largely disappointing [ 404 ].…”

Update on Targeted Therapy in Medullary Thyroid Cancer

“…Several novel strategies are currently being explored for the treatment of patients with RAS mutant cancers. A number of small molecule inhibitors of KRAS-G12C have recently been developed and are being clinically evaluated ( 56 – 58 ). Sotorasib and adagrasib are in phase II trials.…”

“…Sotorasib was investigated in patients with cancers with KRAS-G12C mutation and had a disease response in approximately 30% of patients with non-small cell lung cancer ( 59 ). Other targeted inhibitors of specific mutated activated RAS isoforms are in clinical development ( 58 ). Activating mutations of RAS have also been targeted using immunological approaches.…”