Intrinsic and acquired resistance to MEK1/2 inhibitors in cancer

2014 ◽  
Vol 42 (4) ◽  
pp. 776-783 ◽  
Author(s):  
Matthew J. Sale ◽  
Simon J. Cook
Keyword(s):  
Protein Kinase ◽  
Present Article ◽  
Acquired Resistance ◽  
Mitogen Activated Protein Kinase ◽  
Inhibitor Activity ◽  
Extracellular Signal Regulated Kinase ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Signalling Cascade

Recent clinical data with BRAF and MEK1/2 [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase 1/2] inhibitors have demonstrated the remarkable potential of targeting the RAF–MEK1/2–ERK1/2 signalling cascade for the treatment of certain cancers. Despite these advances, however, only a subset of patients respond to these agents in the first instance, and, of those that do, acquired resistance invariably develops after several months. Studies in vitro have identified various mechanisms that can underpin intrinsic and acquired resistance to MEK1/2 inhibitors, and these frequently recapitulate those observed clinically. In the present article, we review these mechanisms and also discuss recent advances in our understanding of how MEK1/2 inhibitor activity is influenced by pathway feedback.

scholarly journals Isolation and characterization of a Drosophila homologue of mitogen-activated protein kinase phosphatase-3 which has a high substrate specificity towards extracellular-signal-regulated kinase

2001 ◽  
Vol 361 (1) ◽  
pp. 143-151 ◽  
Author(s):  
Sun-Hong KIM ◽  
Hyung-Bae KWON ◽  
Yong-Sik KIM ◽  
Ji-Hwan RYU ◽  
Kyung-Sub KIM ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Kinase ◽  
Expressed Sequence Tag ◽  
Mitogen Activated Protein Kinase ◽  
Calculated Molecular Mass ◽  
Extracellular Signal Regulated Kinase ◽  
Isolation And Characterization ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

A partial C-terminal cDNA sequence of a novel Drosophila mitogen-activated protein kinase phosphatase (MKP), designated DMKP-3, was identified from an epitope expressed sequence tag database, and the missing N-terminal cDNA fragment was cloned from a Drosophila cDNA library. DMKP-3 is a protein of 411 amino acids, with a calculated molecular mass of 45.8kDa; the deduced amino acid sequence is most similar to that of mammalian MKP-3. Recombinant DMKP-3 produced in Escherichia coli retained intrinsic tyrosine phosphatase activity. In addition, DMKP-3 specifically inhibited extracellular-signal-regulated kinase (ERK) activity, but was without a significant affect on c-Jun N-terminal kinase (JNK) and p38 activities, when it was overexpressed in Schneider cells. DMKP-3 interacted specifically with Drosophila ERK (DERK) via its N-terminal domain. In addition, DMKP-3 specifically inhibited Elk-1-dependent trans-reporter gene expression in mammalian CV1 cells, and dephosphorylated activated mammalian ERK in vitro. DMKP-3 is uniquely localized in the cytoplasm within Schneider cells, and gene expression is tightly regulated during development. Thus DMKP-3 is a Drosophila homologue of mammalian MKP-3, and may play important roles in the regulation of various developmental processes.

Integrin and FAK-mediated MAPK activation is required for cyclic strain mitogenic effects in Caco-2 cells

2001 ◽  
Vol 280 (1) ◽  
pp. G75-G87 ◽  
Author(s):  
Wei Li ◽  
Aydin Duzgun ◽  
Bauer E. Sumpio ◽  
Marc D. Basson
Keyword(s):  
Protein Kinase ◽  
Cyclic Strain ◽  
Mitogen Activated Protein Kinase ◽  
Mapk Activation ◽  
Extracellular Signal Regulated Kinase ◽  
Kinase C ◽  
Extracellular Signal ◽  
Mitogen Activated Protein ◽  
Static Conditions

Rhythmic strain stimulates Caco-2 proliferation. We asked whether mitogen-activated protein kinase (MAPK) activation mediates strain mitogenicity and characterized upstream signals regulating MAPK. Caco-2 cells were subjected to strain on collagen I-precoated membranes or antibodies to integrin subunits. Twenty-four hours of cyclic strain increased cell numbers compared with static conditions. MAPK-extracellular signal-regulated kinase (ERK) kinase inhibition (20 μM PD-98059) blocked strain mitogenicity. p38 Inhibition (10 μM SB-202190) did not. Strain rapidly and time-dependently activated focal adhesion kinase (FAK), paxillin, ERK1 and 2, and p38 on collagen. c-Jun NH2-terminal kinase (JNK)1 and 2 exhibited delayed activation. Similar activation occurred when Caco-2 cells were subjected to strain on a substrate of functional antibody to the α2-, α3-, α6-, or β1-integrin subunits but not on a substrate of functional antibody to the α5-subunit. FAK inhibition by FAK397 transfection blocked ERK2 and JNK1 activation by in vitro kinase assays, but pharmacological protein kinase C inhibition did not block ERK1 or 2 activation by strain. Strain-induced ERK signals mediate strain's mitogenic effects and may require integrins and FAK activation.

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