Breakthrough in RAS targeting with pan-RAS(ON) inhibitors RMC-7977 and RMC-6236

•Mutations in the three isoforms of RAS are considered to be responsible for approximately 30% of human cancers.•Until recently, RAS was considered to be largely undruggable.•Multi-selective tri-complex RAS(ON) inhibitors can inhibit all RAS isoforms and potentially bypass mechanisms of resistance.•Significant antitumor activity was shown, especially in non-small cell lung cancer and pancreatic ductal adenocarcinoma.•The agents were well-tolerated, with minimal and transient effects in healthy tissue. The multi-selective tri-complex RAS(ON) inhibitors RMC-7977 and RMC-6236 signal new avenues for RAS targeting. This systematic review aims to comprehensively present the available preclinical and early clinical data on these agents. We screened Medline, Scopus, the ESMO and ASCO conference sites and ClinicalTrials.gov for related studies and found four published preclinical studies and one clinical trial. In these reports, RMC-7977 and RMC-6236 effectively drove tumor suppression, especially in non-small cell lung cancer and pancreatic ductal adenocarcinoma, and minimal effects in healthy tissue were observed. MYC amplification was reported to be a main contributor to the development of resistance. Six trials are currently ongoing, including one randomized trial, and promising results are expected from combination with other agents, such as immune-checkpoint blockers.