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Targeting ERK, an Achilles' Heel of the MAPK pathway, in cancer therapy
Feifei Liu1, Xiaotong Yang1, Meiyu Geng1
1Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
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.
Insights
Targeting the mitogen-activated protein kinases (MAPK) pathway is crucial for cancer therapy. This review highlights ERK inhibitors as a promising strategy to overcome resistance to existing MAPK therapies.
Area of Science:
- Oncology
- Molecular Biology
- Signal Transduction
Background:
- The mitogen-activated protein kinases (MAPK) pathway, also known as the RAS-RAF-MEK-ERK signal cascade, regulates vital cellular processes.
- This pathway is frequently mutated in human cancers, making it a key target for cancer therapy.
- While BRAF and MEK inhibitors have shown clinical success, acquired resistance remains a significant challenge.
Purpose of the Study:
- To review the key protein kinases within the MAPK pathway and their activation mechanisms.
- To summarize the relationship between MAPK member mutations and human cancers.
- To highlight the therapeutic potential of targeting ERK to overcome resistance.
Main Methods:
- Literature review of the MAPK pathway.
- Analysis of kinase activation mechanisms.
- Summary of clinical progress in developing small molecule MAPK kinase inhibitors.
Main Results:
- The MAPK pathway is central to cell proliferation, differentiation, survival, and death.
- Mutations in MAPK pathway components are common in various human cancers.
- Acquired resistance limits the efficacy of current BRAF and MEK inhibitors.
Conclusions:
- Targeting the MAPK pathway remains a critical strategy in cancer treatment.
- ERK inhibitors show potential for overcoming resistance mechanisms associated with upstream MAPK inhibitors.
- Targeting ERK kinase represents a promising future direction for cancer therapy.