Targeting ERK, an Achilles' Heel of the MAPK pathway, in cancer therapy

Abstract

The mitogen-activated protein kinases (MAPK) pathway, often known as the RAS-RAF-MEK-ERK signal cascade, functions to transmit upstream signals to its downstream effectors to regulate physiological process such as cell proliferation, differentiation, survival and death. As the most frequently mutated signaling pathway in human cancer, targeting the MAPK pathway has long been considered a promising strategy for cancer therapy. Substantial efforts in the past decades have led to the clinical success of BRAF and MEK inhibitors. However, the clinical benefits of these inhibitors are compromised by the frequently occurring acquired resistance due to cancer heterogeneity and genomic instability. This review briefly introduces the key protein kinases involved in this pathway as well as their activation mechanisms. We also generalize the correlations between mutations of MAPK members and human cancers, followed by a summarization of progress made on the development of small molecule MAPK kinases inhibitors. In particular, this review highlights the potential advantages of ERK inhibitors in overcoming resistance to upstream targets and proposes that targeting ERK kinase may hold a promising prospect for cancer therapy.

ERK inhibition effectively overcomes acquired resistance of epidermal growth factor receptor‐mutant non–small cell lung cancer cells to osimertinib

“…Therefore, targeting ERK is as effective as MEK inhibition in overcoming acquired resistance to osimertinib, reinforcing our notion that targeting MEK/ERK signaling is a very effective therapeutic strategy for overcoming osimertinib acquired resistance. There are several ERK small‐molecule inhibitors, including those used in the current study, that have been tested or are being tested in clinical phase 1 and 2 trials, among which both GDC0994 and VRT752271 have demonstrated preliminary antitumor activity . Our findings warrant future clinical testing of these ERK inhibitors in combination with osimertinib or other third‐generation EGFR‐TKIs for overcoming acquired resistance to these EGFR‐TKIs.…”

“…There are several ERK small-molecule inhibitors, including those used in the current study, that have been tested or are being tested in clinical phase 1 and 2 trials, among which both GDC0994 and VRT752271 have demonstrated preliminary antitumor activity. 14,15 Our findings warrant future clinical testing of these ERK inhibitors in combination with osimertinib or other third-generation EGFR-TKIs for overcoming acquired resistance to these EGFR-TKIs. ERK inhibition, like MEK inhibition in our previous report, 7 elevated Bim levels concurrently with enhanced reduction of Mcl-1 levels when combined with osimertinib in osimertinib-resistant cell lines.…”

Deciphering UV‐induced DNA Damage Responses to Prevent and Treat Skin Cancer

“…ROS generated by UV activate a number of signaling pathways that are related to inflammation and carcinogenesis (136). Examples of oncogenic signaling activated by UV‐induced ROS include the mitogen‐activated protein kinase/extracellular signal‐regulated kinase (MAPK/ERK) pathway (136,142), which is overactive in many cancers (143), epidermal growth factor receptor (EGFR) (144), p38 MAPK (142), activating protein‐1 (AP‐1) (136) and NF‐κB (136). Activation of NRF2, a transcription factor that induces antioxidant defense, decreases ROS levels and prevents ROS‐induced mutations following UV irradiation, thereby inhibiting skin carcinogenesis (145).…”

Positive feedback loop of regulating ERK phosphorylation in mESCs mediated by Etv5-Tet2-Fgfr2 axis

“…FGF-ERK signaling pathway plays fundamental roles in proliferation, differentiation, apoptosis, migration, and genome stability during development (Ornitz and Itoh, 2015). However, aberrant activation of FGF-ERK signaling pathway often leads to tumorigenesis or carcinogenesis (Liu et al, 2018). Our findings in this study will provide useful clues to understand the cell fate determination during early embryo development and explore new strategies for cancer treatment.…”