TY - JOUR
T1 - MEK inhibitor resistance mechanisms and recent developments in combination trials
AU - Kun, E.
AU - Tsang, Y. T.M.
AU - Ng, C. W.
AU - Gershenson, D. M.
AU - Wong, K. K.
N1 - Publisher Copyright:
© 2020 The Author(s)
PY - 2021/1
Y1 - 2021/1
N2 - 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.
AB - 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.
KW - Drug combination trials
KW - MEK inhibitors
KW - Mechanisms of Adaptive Resistance
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U2 - 10.1016/j.ctrv.2020.102137
DO - 10.1016/j.ctrv.2020.102137
M3 - Review article
C2 - 33340965
AN - SCOPUS:85097748195
SN - 0305-7372
VL - 92
JO - Cancer treatment reviews
JF - Cancer treatment reviews
M1 - 102137
ER -