Mutations That Confer Drug-Resistance, Oncogenicity and Intrinsic Activity on the ERK MAP Kinases—Current State of the Art

Abstract

Unique characteristics distinguish extracellular signal-regulated kinases (Erks) from other eukaryotic protein kinases (ePKs). Unlike most ePKs, Erks do not autoactivate and they manifest no basal activity; they become catalysts only when dually phosphorylated on neighboring Thr and Tyr residues and they possess unique structural motifs. Erks function as the sole targets of the receptor tyrosine kinases (RTKs)-Ras-Raf-MEK signaling cascade, which controls numerous physiological processes and is mutated in most cancers. Erks are therefore the executers of the pathway’s biology and pathology. As oncogenic mutations have not been identified in Erks themselves, combined with the tight regulation of their activity, Erks have been considered immune against mutations that would render them intrinsically active. Nevertheless, several such mutations have been generated on the basis of structure-function analysis, understanding of ePK evolution and, mostly, via genetic screens in lower eukaryotes. One of the mutations conferred oncogenic properties on Erk1. The number of interesting mutations in Erks has dramatically increased following the development of Erk-specific pharmacological inhibitors and identification of mutations that cause resistance to these compounds. Several mutations have been recently identified in cancer patients. Here we summarize the mutations identified in Erks so far, describe their properties and discuss their possible mechanism of action.

Impact of Conventional and Atypical MAPKs on the Development of Metabolic Diseases

“…They are also involved in actin polymerization via their interaction with different actin regulatory proteins [ 16 ]. Additionally, ERK1/2 are implicated in the development of multiple types of cancers (reviewed in [ 17 , 18 ]). Consistent with their critical roles in tumorigenesis, targeting these enzymes present nowadays an outstanding interest for different therapeutic purposes [ 18 ].…”

Two Targets, One Hit: new Anticancer Therapeutics to Prevent Tumorigenesis Without Cardiotoxicity

“…The MAPK/ERK pathway is one of the major targets of anti-tumor therapies in several malignancies as gain-of-function mutations of this pathway are collectively associated with more than 90% of cancers ( Nissan et al, 2013 ; Smorodinsky-Atias et al, 2020 ). The cascade involves the sequential activation of receptor tyrosine kinases (RTK), RAS GTPases, RAF kinases (MAP3K), MEK (MAP2K), which ultimately phosphorylates ERK (MAPK) ( Lee et al, 2020 ).…”

“…Therapeutic targeting of ERK is of key interest since ERK inhibitors (ERKi) have the potential to overcome common drug resistance to “upstream” MEK/RAF/RAS inhibitors ( Ryan and Corcoran, 2018 ; Smorodinsky-Atias et al, 2020 ). Indeed, ERKi therapies are expected to show greater antitumor efficacy in advanced metastatic and multidrug-resistant tumors with reactivated MAPK signaling, however, their broad clinical use is limited ( Lee et al, 2020 ).…”

Structural mechanism of inhibitor-resistance by ERK2 mutations

“…ERK remains inactive until two amino residues within the activation loop are phosphorylated by mitogen-activated kinase (MEK) in response to extracellular growth factors. The ERK signaling pathway is involved in regulating cell proliferation, differentiation, and survival (Chaikuad et al, 2014;Goetz et al, 2014;Tong and Seeliger, 2015;Jaiswal et al, 2018;Pegram et al, 2019;Smorodinsky-Atias et al, 2020). It has been found that the tumor is resistant to ERK inhibitor treatment when the patient is continuously administered a small molecule inhibitor.…”