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Page 6 Conroy et al. Cancer Drug Resist 2021;4:543-58 https://dx.doi.org/10.20517/cdr.2021.07

G13D
KRAS mutation
Immunotherapy
A study of Avelumab, Binimetinib and Talazoparib in patients with locally advanced or Avelumab Solid tumours KRAS or NRAS mutant NCT03637491
metastatic RAS-mutant Solid Tumors I/II Binimetinib
Talazoparib
A study of Binimetinib + Nivolumab plus or minus Ipilimumab in patients with previously Binimetinib Colorectal cancer RAS mutations NCT03271047
treated Microsatellite stable metastatic colorectal cancer with RAS mutation I/II Nivolumab
ipilimumab

RAS-mutated head and neck squamous cell carcinoma xenograft models and is undergoing clinical development in advanced head and neck cancers
harbouring activating H-RAS mutations (NCT02383927) . These efforts highlight the differences between RAS isoforms and the need for a tailored, isoform-
[26]
specific approach to clinical trial design.

Salirasib is an S-trans, trans-farnesylthiosalicylic acid and a novel oral RAS inhibitor which competes with farnesylated RAS for binding sites on membranes. A

recent trial demonstrated encouraging activity in patients with advanced solid tumours including a subset with K-RAS mutations . A further target is
[27]
isoprenylcysteine carboxyl methyltransferase (ICMT), an enzyme at the endoplasmic reticulum which increases RAS membrane affinity. It lacks homology
with other protein methyltransferases, which adds to its specificity as a target. While agents that target ICMT have been isolated, and have demonstrated

promising results in vitro against cancer cell lines, they have not been tested in the clinical setting . Palmitoylation, the modification by the fatty acid
[28]
palmitate, is necessary for the membrane interactions of H-RAS and N-RAS. Depalmitoylation inhibitors and palmitoyl acyltransferases have been described
as having activity against RAS, but uncertainty regarding their specificity and concern about off-target effects, have impeded their further clinical
development . Many other proteins are modified by prenylation and farnesylation to ensure their correct subcellular localization, which makes off-target
[4]
effects unavoidable even for highly specific inhibitors. Moreover, RAS can also signal from endomembranes (Golgi apparatus, endoplasmic reticulum) in
addition to the plasma membrane [29,30] . It is unclear how localization inhibitors affect RAS signalling from different subcellular compartments.

Inhibitors of RAS effector signalling
Given the historic difficulties in directly targeting RAS, many efforts focused instead on inhibiting the downstream signal transduction pathways, either at a
single point or as a combined approach targeting different nodal points. RAS effector families are involved in cancer initiation and maintenance, and it was
hoped that inhibition of downstream proteins within these pathways could be an effective means of countering RAS-mediated oncogenesis . These
[28]
approaches have largely failed, perhaps mainly due to the inherent complexity and redundancy within these networks, but also due to a lack of specificity in
the selection of inhibitors as well as isoform homogeneity within each subpopulation. In addition, the concept of linear pathways is misleading and has given
way to that of signalling networks, whereby activated kinases interact via RAS (or other GTPases) with a large variety of signalling molecules resulting in highly

interconnected networks.