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Page 8 Conroy et al. Cancer Drug Resist 2021;4:543-58 https://dx.doi.org/10.20517/cdr.2021.07

ERK upregulation through MEK appears to be the predominant method of resistance to BRAF directed
monotherapy and we have seen both in preclinical and clinical studies that concurrent inhibition of BRAF
[47]
and MEK can decrease acquired resistance and delay progression . In RAS-mutant tumours, MEK
inhibition as monotherapy has failed to demonstrate meaningful benefits largely due to the induction of
feedback loops similar to those when RAF inhibitors are use in this setting . Trametinib, Cobimetinib and
[48]
Binimetinib are allosteric, non-ATP competitive inhibitors of MEK1 and MEK2, and are used in
combination with RAF inhibitors in the treatment of melanoma. A number of trials have failed to show
clinical benefit for MEK inhibition in advanced KRAS-mutant pancreatic, colorectal and non-small cell lung
cancer [49-51] . One possible explanation for this is that inhibition of the ERK pathway induces autophagy, a
[52]
process of cellular recycling that protects cells from the cytocidal effects of pathway inhibition . Pancreatic
[53]
cancer cells in particular utilize autophagy for growth and as a means of resistance to ERK inhibition .
Combining downstream MEK inhibition with hydroxychloroquine - an inhibitor of autophagy - displayed
synergistic anti-proliferative effects against pancreatic ductal adenocarcinoma (PDA) cell lines and
promoted striking regression of PDA xenografts from 2 patients with PDA which was superior to (standard
of care) gemcitabine plus nab-paclitaxel chemotherapy. Highly encouraging clinical responses were also
seen with this commercially available drug combination and clinical trials are ongoing [52,54] .

ERK pathway: With ERK being the final kinase in the RAF-MEK-ERK pathway it would appear to be an
attractive target to inhibit in RAS or RAF mutant tumours. Based on previous preclinical studies of the
compound SCH-772984, a dual ERK1/2 inhibitor which demonstrated a reduction of phosphorylated ERK
[55]
in a number of RAS-mutant cancer cell lines, an oral version MK-8353 was developed for clinical testing .
In a Phase I study, however, with 26 patients with advanced K-RAS or N-RAS mutated tumours, no
objective responses were seen. It is now being tested in combination with a MEK inhibitor (selumetinib)
and the anti-PD-1 inhibitor pembrolizumab in patients with RAS-mutant cancers. In K-RAS-mutant
tumour models, ERK inhibitors such as GDC-0944 have shown efficacy in combination with the MEK
inhibitor cobimetinib . Phase I studies of the combination were stopped prematurely due to toxicity .
[56]
[57]
The ERK inhibitor was studied as monotherapy in a Phase I trial and appeared tolerable . In this study, 14
[58]
patients had K-RAS-mutant advanced malignancies and of those 4 had stable disease and 10 had
progression. ERK pathway suppression detected with NanoString gene expression was observed more
commonly in those with BRAF-mutant tumours compared to those with KRAS-mutant tumours.

Ulixertinib is another ATP competitive ERK1/2 inhibitor that has shown clinical efficacy in N-RAS-mutant
[59]
melanoma . This in combination with nab-paclitaxel has been examined in a Phase 1 study in patients
with advanced pancreas cancer and results are awaited (NCT02608229). Other studies are underway
examining its role as monotherapy and in combination with other agents in patients with genetic alteration
in the ERK pathway (NCT03698994, NCT04145297). LY-3214996 is a selective inhibitor of ERK1 and
[60]
ERK2 . Unfortunately, however, in a Phase I study of this agent, only one patient with advanced RAS-
[60]
mutant cancer had stable disease and the remaining patients had progressive disease . KO-947, similarly a
selective ERK1/2 inhibitor, demonstrated potent and sustained reduction in phosphorylated ERK in vitro in
RAS-mutant cell lines . This is now in clinical studies for patients with advanced RAS- or RAF-mutant
[61]
tumours (NCT03051035).

PI3K pathway: The other major target of RAS effector signalling is the PI3K-AKT-mTOR pathway. PI3K is
implicated in RAS-dependent cancer initiation and maintenance. While there are many inhibitors of this
[62]
signalling pathway under investigation , they have demonstrated little activity as monotherapy in RAS-
mutant cancers. KRAS and BRAF mutations are predictive of resistance to mTOR inhibition . Moreover,
[63]
inhibition of mTOR may lead to the upregulation and activation of MEK-ERK pathways. Therefore, the