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Page 6 of 19 Cordover et al. J Cancer Metastasis Treat 2020;6:45 I http://dx.doi.org/10.20517/2394-4722.2020.101

transduction. ERK is involved in the regulation of many cellular processes, such as proliferation and
[27]
differentiation, and its increased activity is often implicated in several human cancers . ERK is activated
by its upstream effector MEK through phosphorylation [Figure 1]. ERK has roles in both the cytoplasm and
the nucleus. In the cytoplasm, ERK modulates key cytoskeletal proteins that affect motility, metabolism,
[28]
and cell adhesion . ERK exerts its nuclear functions by dimerizing and localizing to the nucleus once it is
activated. In the nucleus, ERK phosphorylates and subsequently activates a number of transcription factors
[29]
that are involved in cell proliferation and survival . Due to its aberrant expression in several cancers, it is
being studied as a potential therapeutic option in cancers with B-Raf and N/K-Ras mutations .
[27]
As discussed earlier in this review, BRAF mutations are common in an array of human cancers, most
notably in melanoma. BRAF inhibitors are shown to be promising in the short-term, but ultimately, are
ineffective at blocking cancer cell survival and proliferation. BRAF/MEK dual inhibition is associated with
an increased anti-tumor response. Unfortunately, up to 70% of tumors treated with a BRAF/MEK dual
inhibition strategy experience ERK/MAPK pathway reactivation and evade treatment . Hence, novel
[30]
strategies that target the Ras/ERK pathway in cancers with BRAF mutations are sought. Once such novel
inhibitor that targets this pathway is the ERK inhibitor ulixertinib. Recent studies report on the efficacy
of ulixertinib in solid malignancies in a phase I clinical trial. Ulixertinib is a highly potent, reversible,
and selective ATP-competitive inhibitor of ERK1/2. Previous evidence shows that ulixertinib reduces
[27]
tumorigenesis in BRAF- and Ras-mutant xenograft models . The results of the phase I clinical trial
provide evidence that ulixertinib is effective in cancers with a diverse assortment of BRAF mutations. In
addition, in melanoma patients whose tumors were resistant to BRAF/MEK dual inhibition, ulixertinib
is shown to exert anticancer effects . Due to the success of ulixertinib thus far, the inhibitor is being
[31]
[31]
investigated in combination with other inhibitors, such as BRAF inhibitor dabrafenib .
[32]
Despite the initial success of ulixertinib, challenges remain with ERK inhibitors. A 2018 study by Jaiswal et al.
conveyed that ERK inhibitors, when used as a single agent, are likely to confer drug-acquired resistance.
The researchers looked at five different ATP-competitive ERK inhibitors, including ulixertinib, to determine
the mechanism behind acquired resistance to ERK inhibition. Upon treatment with ERK inhibitors, RAS-/
RAF-mutant cell lines acquired several mutations that affect the binding of ERK inhibitors to their target,
[32]
preventing the hindrance of ERK1/2 activity . The authors also displayed the novel finding that ERK2
[32]
amplification is a mechanism of resistance to ERK inhibitors . Hence, due to the diverse mechanisms of
resistance to ERK inhibition, ERK inhibitors are being looked at in combination with other inhibitors of the
[32]
ERK/MAPK pathway. Jasiwal et al. suggested that ERK inhibitors in combination with MEK inhibitors
may prove advantageous in treating malignancies with acquired resistance to RAF/MEK inhibitors. In
addition, RTKs and components of the PI3K/AKT/mTOR pathway were identified as mediators of acquired
resistance. As such, combination therapy involving ERK inhibitors with either inhibitors of the PI3k/AKT/
mTOR pathway or RTK inhibitors, such as those that target members of the HER family, may prevent the
development of resistance . Overall, the use of ERK inhibitors as part of combination therapy is promising
[32]
for the treatment of cancers with mutations in the ERK/MAPK pathway.

HER2/NEU/ERBB2
The RTK EGFR consists of four members, also known as the human epidermal growth factor receptor
(HER) or ErbB family. These receptors include HER1 (also called ErbB1 or EGFR), HER2 (also called
ErbB2), HER3 (ErbB3), and HER4 (ErbB4). Under normal conditions, the members of this family of RTKs
are known to have important roles in development. Like other RTKs, the HER/ErbB family of receptors are
activated by binding to ligands on their extracellular domains, which leads them in turn to form dimers
with each other or with other HER/ErbB family members. Upon dimerization, intracellular signaling
pathways are activated, leading to a response to the signal. HER2/ErbB2 functions differently from the
other members because it does not require a ligand to form a dimer. Although it does not directly bind any