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Page 10 Conroy et al. Cancer Drug Resist 2021;4:543-58 https://dx.doi.org/10.20517/cdr.2021.07

of sotorasib (AMG510) demonstrated promising anticancer activity in patients with advanced solid tumours
harbouring K-RAS(G12C) mutations. 129 patients were treated on the dose escalation study, 59 with
NSCLC, 42 with colorectal cancer and 28 with other solid tumours. Sotorasib appeared to be well tolerated
with 11.6% of grade 3 or 4 toxicity. 32.2% of the NSCLC had an objective response with a total of 88.1%
having a response or stable disease. The median progression free survival was 6.3 months. In the colorectal
cohort 7.1% had a confirmed response with 73.8% having a response or stable disease with a median PFS of
4 months . This study represented the first clinical trial demonstrating objective response to direct KRAS
[78]
inhibition. On December 8, 2020 the FDA granted Breakthrough Therapy designation for its investigational
K-RAS(G12C) inhibitor, sotorasib, for the treatment of patients with locally advanced or metastatic NSCLC
with K-RAS(G12C) mutations, as determined by an FDA-approved test, following at least one prior
systemic therapy. Preclinical studies have also demonstrated that sotorasib was able to clear colon cancer
[79]
from mice when given in combination with checkpoint inhibitors . There is a Phase 1/2 study under way
of sotorasib in solid tumours which will include a combination arm of sotorasib with an anti(PD-1/L1)
(NCT03600883).

Adagrasib (MRTX849) is an additional agent under investigation in this field. It is a potent, highly selective
inhibitor of KRAS(G12C) . A Phase 1/2 study of adagrasib monotherapy in patients with pretreated
[80]
NSCLC demonstrated an overall response rate of 45% and a high disease control rate . This multiple-
[81]
expansion-cohort trial is ongoing, investigating the use of adagrasib combined with pembrolizumab in
NSCLC, afatinib in NSCLC or cetuximab in colorectal cancer. Research on this agent in nonclinical models
has also demonstrated mechanisms of resistance, including KRAS nucleotide cycling and pathways that
induce feedback reactivation or bypass KRAS dependence .
[80]

K-RAS(G12C) mutations only account for a small proportion of KRAS mutations that are found in cancer
and are primarily found in lung cancer. As these irreversible allosteric inhibitors block RAS signalling by
exclusively binding to the cysteine residue that results from the specific mutation, this limits their
application to the particular allele they target. To target KRAS(G12D) and KRAS(G12V) different
approaches are needed as these mutants lack the cysteines needed in the active state.

Attempting to design and develop drugs specifically targeting each individual RAS mutation would be
extremely challenging and time-consuming, so direct targeting of ligand binding sites conserved on all RAS
proteins (KRAS4A, 4B, NRAS and HRAS) has been thought to be one potential method of inhibiting RAS
across all mutation and tumour types. In vitro studies have shown that Compound 3144, a molecule that
[82]
binds a conserved residue Asp38 in switch-I, can block RAS effector binding . This compound suppresses
the growth of KRAS(G13D) tumours in vivo. A major concern, however, is that pan-inhibition of RAS
potentially may lead to considerable toxicity as normal cellular function is reliant on RAS signalling in non-
cancerous cells . Models by which the deletion of all three RAS isoforms is carried out are not compatible
[83]
with life, and therefore a pan inhibition of RAS in humans is likely to result in significant off-target toxicity.
Nevertheless, it has been suggested that if such a compound were optimised for greater potency and
specificity, this would be a viable approach .
[82]

Nucleotide exchange inhibition: In order to cycle between active GTP-bound and inactive GDP-bound
states, RAS possesses intrinsic guanine nucleotide exchange and GTP hydrolysis activities. This cycling and
exchange are accelerated by GEF and by GAPs, both of which change the activation state of RAS through
covalent modifications. Upon activation of GEFs, nucleotide binding is destabilized and GDP is released. As
GTP is much more prevalent than GDP in the cell, this loss of GDP leads to a transient formation of RAS-
[4]
GTP, the active state . GTP binding and activation of RAS leads to conformational changes in it, allowing it