MEK inhibitor resistance mechanisms and recent developments in combination trials. (January 2021)

• Record Type: Journal Article
• Authors: Kun, E.; Tsang, Y.T.M.; Ng, C.W.; Gershenson, D.M.; Wong, K.K.
• Is Part Of: Cancer treatment reviews. Volume 92(2021)
• Publication Date: 2021-01
• Subjects: MEK inhibitors -- Mechanisms of Adaptive Resistance -- Drug combination trials; Cancer -- Periodicals; Cancer -- Treatment -- Periodicals; Neoplasms -- therapy -- Periodicals; Cancer -- Périodiques; Cancer -- Traitement -- Périodiques; Cancer -- Treatment; Electronic journals; Periodicals; 616.99406
• DOI: 10.1016/j.ctrv.2020.102137
• Languages: English
• ISSNs: 0305-7372

Abstract

Highlights: A variety of MEK inhibitors have been tested as a single agent in clinical trials and shown to be limited to certain types of cancers. Side effects from MEK inhibition can be significant but are more tolerable than effects from conventional cancer therapies. Novel mechanisms of adaptive resistance to MEK inhibitor have been discovered in different cancers. Combination clinical trials are being developed to overcome MEK inhibitor resistance. Abstract: The mitogen-activated protein kinase (MAPK) pathway plays a vital role in cellular processes such as gene expression, cell proliferation, cell survival, and apoptosis. Also known as the RAS-RAF-MEK-ERK pathway, the MAPK pathway has been implicated in approximately one-third of all cancers. Mutations in RAS or RAF genes such as KRAS and BRAF are common, and these mutations typically promote malignancies by over-activating MEK and ERK downstream, which drives sustained cell proliferation and uninhibited cell growth. Development of drugs targeting this pathway has been a research area of great interest, especially drugs targeting the inhibition of MEK. In vitro and clinical studies have shown promise for certain MEK inhibitors (MEKi), and MEKi have become the first treatment option for certain cancers. Despite promising results, not all patients have a response to MEKi, and mechanisms of resistance typically arise in patients who do have a positive initial response. This paper summarizes recent developments regarding MEKi, the mechanisms of adaptive resistance to MEKi, and the potential solutions to the issue of adaptive MEKi resistance.