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MEK in cancer and cancer therapy
Cindy Neuzillet1, Annemilaï Tijeras-Raballand2, Louis de Mestier3
1INSERM U728 and Department of Medical Oncology, Beaujon University Hospital, AP-HP-PRES, Paris 7 Diderot, 100 boulevard du Général Leclerc, 92110 Clichy, France; Department of Gastroenterology and Pancreatology, Beaujon University Hospital, AP-HP-PRES, Paris 7 Diderot, 100 boulevard du Général Leclerc, 92110 Clichy, France.
Abstract:
The mitogen-activated extracellular signal-regulated kinase (MEK) pathway is one of the best-characterized kinase cascades in cancer cell biology. It is triggered by either growth factors or activating mutations of major oncogenic proteins in this pathway, the most common being Ras and Raf. Deregulation of this pathway is frequently observed and plays a central role in the carcinogenesis and maintenance of several cancers, including melanoma, pancreatic, lung, colorectal, and breast cancers. Targeting these kinases offers promise of novel therapies. MEK inhibitors (MEKi) are currently under evaluation in clinical trials and many have shown activity. In this review, we comprehensively examine the role of the MEK pathway in carcinogenesis and its therapeutic potential in cancer patients, with a focus on MEKi. We describe the clinical perspectives of MEKi in the two main models of Ras-ERK driven tumors, BRAF-mutant ("addicted" to the pathway) and KRAS-mutant (non-"addicted"). We also highlight the known mechanisms of resistance to MEKi and emerging strategies to overcome it.
Insights
The mitogen-activated extracellular signal-regulated kinase (MEK) pathway is crucial in various cancers. MEK inhibitors show promise as cancer therapies, with ongoing research into their effectiveness and resistance mechanisms.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- The mitogen-activated extracellular signal-regulated kinase (MEK) pathway is a key signaling cascade in cancer development.
- Deregulation of the MEK pathway, often initiated by Ras or Raf mutations, is implicated in numerous cancers like melanoma, lung, and breast cancer.
Purpose of the Study:
- To review the role of the MEK pathway in carcinogenesis.
- To examine the therapeutic potential of MEK inhibitors (MEKi) in cancer treatment.
- To discuss clinical perspectives of MEKi in BRAF-mutant and KRAS-mutant tumors and resistance mechanisms.
Main Methods:
- Comprehensive literature review of the MEK pathway in cancer.
- Analysis of clinical trial data for MEK inhibitors.
- Examination of resistance mechanisms to MEKi.
Main Results:
- The MEK pathway is central to the development and progression of various cancers.
- MEK inhibitors (MEKi) demonstrate therapeutic activity in clinical trials.
- Understanding resistance mechanisms is critical for optimizing MEKi efficacy.
Conclusions:
- Targeting the MEK pathway with MEKi represents a promising therapeutic strategy for cancer patients.
- Clinical application of MEKi varies between BRAF-mutant and KRAS-mutant tumors.
- Further research into overcoming MEKi resistance is essential for improving patient outcomes.
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