RAS- targeted therapies: is the undruggable drugged?
RAS-targeted therapies is the undruggable drugged.pdf
Amanda R. Moore 1, Scott C. Rosenberg1, Frank McCormick2 and Shiva Malek1 ✉
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, KRASG12C, 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.
Fig. 1 | clinical development of inhibitors for RAS-mutant tumours. Activation of receptor tyrosine kinases, such as
members of the epidermal growth factor receptor (EGFR) family, promotes the exchange of GDP for GTP in RAS, thereby
activating RAS. Inhibition of EGFR can reduce this activation. Inhibition of SOS or SHP2 decreases the rate of GDP–GTP
exchange and reduces the GTP- bound RAS population. Mutant RAS proteins accumulate in the GTP- bound state.
A number of approaches have been developed to directly inhibit RAS, including covalent allele- specific inhibitors that
bind to KRAS- G12C. GTP- bound RAS activates downstream signalling by binding to the RAS- binding domain of effector
proteins, such as RAF and p110, to activate the MAPK and PI3K signalling cascades, respectively. Both the MAPK and PI3K
signalling cascades can be inhibited at each kinase tier. Data compiled from ClinicalTrials.gov and AccessData.FDA.gov.
aOnly effective against monomeric BRAF (BRAF- V600E/K). bApproved for the treatment of BRAF- mutant melanoma.
cApproved for the treatment of paediatric patients with NF1 mutations.
Fig. 2 | Frequency and distribution of rAs mutations in human cancers. Human cancers differ in which has the
most frequently mutated RAS isoform, codon and amino acid substitution. a | Distribution of RAS isoform (KRAS, NRAS
and HRAS) mutations across tumour types and the frequency of the RAS mutation by isoform in each tumour type.
b | Percentages of KRAS mutations that are in codon 12 by tissue type for pancreatic, colorectal and lung adenocarcinoma,
and the percentage of NRAS mutations that are in codon 61 for melanoma. The distributions of amino acid substitutions
at the mutated codon (12 or 61) for each tissue type are shown in pie charts beside the relevant organ. Data acquired
from The Cancer Genome Atlas (pan- Cancer) from cBioPortal and from Project GENIE269 (GENIE v7.0 public).