RAS-targeted therapies: is the undruggable drugged?

Abstract

RAS (KRAS, NRAS and HRAS) is the most frequently mutated gene family in cancers, and, consequently, investigators have sought an effective RAS inhibitor for more than three decades. Even 10 years ago, RAS inhibitors were so elusive that RAS was termed 'undruggable'. Now, with the success of allele-specific covalent inhibitors against the most frequently mutated version of RAS in non-small-cell lung cancer, KRAS G12C , we have the opportunity to evaluate the best therapeutic strategies to treat RAS-driven cancers. Mutation-specific biochemical properties, as well as the tissue of origin, are likely to affect the effectiveness of such treatments. Currently, direct inhibition of mutant RAS through allele-specific inhibitors provides the best therapeutic approach. Therapies that target RAS-activating pathways or RAS effector pathways could be combined with these direct RAS inhibitors, immune checkpoint inhibitors or T cell-targeting approaches to treat RAS-mutant tumours. Here we review recent advances in therapies that target mutant RAS proteins and discuss the future challenges of these therapies, including combination strategies. RAS (KRAS, NRAS and HRAS) is the most frequently mutated gene family in cancers.Mutations in KRAS are known drivers of three of the most lethal cancers (lung cancer, colorectal cancer (CRC) and pancreatic cancer). For more than three decades, development of effective therapeutics to inhibit RAS-driven oncogenesis has eluded the field and RAS was thought to be 'undruggable'. However, a clinically approved mutant selective KRAS therapy is now within sight as the FDA has granted an allele-specific covalent inhibitor, AMG 510, Fast Track designation 1 . AMG 510 binds to KRAS-G12C, the RAS mutatant most commonly found in non-small-cell lung tumours. This successful inhibition of KRAS-G12C, has given hope that a range of mutant RAS allele-specific targeted therapies could become therapeutically tractable.In normal cells, RAS is activated at the membrane downstream of growth factor receptors, including members of the epidermal growth factor receptor (EGFR) family (FIG. 1). This

Immune modulatory effects of oncogenic KRAS in cancer

“…Unfortunately, monotherapies targeted to RAS oncogenes have mostly failed following initial response owing to resistance occurring via different mechanisms such as feedback reactivation of RAS-downstream pathways. Nevertheless, substantial advances have been made lately, introducing promising compounds where some are undergoing clinical trials (reviewed in Moore et al 81 ). This includes approaches targeting KRAS G12C oncoproteins or blocking GTP loading of KRAS oncoproteins, which indicate that direct targeting of KRAS might be achievable eventually, even though acquired resistance phenomena against these novel therapies might be inevitable 82 .…”

Cancer biology functional genomics: From small RNAs to big dreams

“…Activating mutations in KRAS, NRAS, and HRAS, which encode for members of the RAS family of proteins, occur at high prevalence in many cancer types, particularly subtypes of lung and pancreatic cancers. 115 One of the earliest shRNA screens first focused on identifying genes that may alter RAS activity in the absence of a mutation using modified primary fibroblasts, with enhanced potential to transform. The screen identified the transcription factor PITX1 as a putative suppressor of RAS activity, 116 a finding subsequent studies of hepatocarcinogenesis confirmed.…”

The compound 2‑benzylthio‑5,8‑dimethoxynaphthalene‑1,4‑dione leads to apoptotic cell death by increasing the cellular reactive oxygen species levels in Ras‑mutated liver cancer cells

“…Research into drugs targeting Ras has made progress (20). Certain research demonstrated that 2,3-dichloro-1,4-naphthoquinone inhibited the growth of N-Ras-mutant melanoma (21), while 2-(2' ,4'-dihydroxyphenyl)-8-hydroxy-1,4-naphthoquinone and 5-hydroxy-2-(2,4-dihydroxyphenyl)naphthalene-1,4-dione inhibited Apc/K-Ras-mutant mouse organoid differentiation capacity (22).…”