From basic research to clinical development of MEK1/2 inhibitors for cancer therapy

The Hallmarks of Cancer

2000 • 27,569 citations

Mutations of the BRAF gene in human cancer

2002 • 10,249 citations

Opposing Effects of ERK and JNK-p38 MAP Kinases on Apoptosis

1995 • 5,334 citations

Mitogen-Activated Protein (MAP) Kinase Pathways: Regulation and Physiological Functions*

2001 • 3,897 citations

PD 098059 Is a Specific Inhibitor of the Activation of Mitogen-activated Protein Kinase Kinase in Vitro and in Vivo

1995 • 3,456 citations

ERBB receptors and cancer: the complexity of targeted inhibitors

2005 • 3,200 citations

Identification of a Novel Inhibitor of Mitogen-activated Protein Kinase Kinase

1998 • 3,026 citations

A synthetic inhibitor of the mitogen-activated protein kinase cascade.

1995 • 2,723 citations

Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells

1994 • 1,999 citations

Discovery and development of sorafenib: a multikinase inhibitor for treating cancer

2006 • 1,693 citations

Hyperactive Ras in developmental disorders and cancer

2007 • 1,549 citations

Mitogen-Activated Protein (MAP) Kinase Pathways: Regulation and Physiological Functions

2001 • 1,385 citations

Differential regulation and properties of MAPKs

2007 • 1,376 citations

Transformation of Mammalian Cells by Constitutively Active MAP Kinase Kinase

1994 • 1,370 citations

BRAF mutation predicts sensitivity to MEK inhibition

2005 • 1,312 citations

Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers

2008 • 1,306 citations

Multiple Ras-dependent phosphorylation pathways regulate Myc protein stability

2000 • 1,275 citations

The extracellular signal-regulated kinase: Multiple substrates regulate diverse cellular functions

2006 • 1,247 citations

Phosphorylation and Functional Inactivation of TSC2 by Erk

2005 • 1,229 citations

Cyclin D1 Expression Is Regulated Positively by the p42/p44 and Negatively by the p38/HOG Pathway

1996 • 1,203 citations

Targeting the mitogen-activated protein kinase cascade to treat cancer

2004 • 1,093 citations

The ERK1/2 mitogen-activated protein kinase pathway as a master regulator of the G1- to S-phase transition

2007 • 1,044 citations

Mitogen-activated protein kinases p42mapk and p44mapk are required for fibroblast proliferation.

1993 • 992 citations

Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo

1999 • 970 citations

Guilty as charged

2004 • 783 citations

Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase

2004 • 737 citations

ERK implication in cell cycle regulation

2006 • 712 citations

Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors

1999 • 688 citations

Insulin-like Growth Factor 1 Inhibits Apoptosis Using the Phosphatidylinositol 3′-Kinase and Mitogen-activated Protein Kinase Pathways

1997 • 662 citations

ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation

2008 • 653 citations

Defective Thymocyte Maturation in p44 MAP Kinase (Erk 1) Knockout Mice

1999 • 641 citations

Multicenter Phase II Study of the Oral MEK Inhibitor, CI-1040, in Patients With Advanced Non-Small-Cell Lung, Breast, Colon, and Pancreatic Cancer

2004 • 631 citations

MEK1 mutations confer resistance to MEK and B-RAF inhibition

2009 • 622 citations

Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition

2004 • 588 citations

Phase I Pharmacokinetic and Pharmacodynamic Study of the Oral, Small-Molecule Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor AZD6244 (ARRY-142886) in Patients With Advanced Cancers

2008 • 569 citations

Biological Characterization of ARRY-142886 (AZD6244), a Potent, Highly Selective Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor

2007 • 556 citations

Activation of the Protein Kinase ERK5/BMK1 by Receptor Tyrosine Kinases

1999 • 518 citations

Mechanism of p38 MAP kinase activation in vivo

2003 • 466 citations

Integrating the MAP kinase signal into the G1 phase cell cycle machinery

2000 • 458 citations

Tumour cell survival signalling by the ERK1/2 pathway

2008 • 455 citations

Molecular mechanisms mediating mammalian mitogen-activated protein kinase (MAPK) kinase (MEK)-MAPK cell survival signals.

2001 • 425 citations

PI3K Pathway Activation Mediates Resistance to MEK Inhibitors in KRAS Mutant Cancers

2009 • 424 citations

Targeted Expression of BRAFV600E in Thyroid Cells of Transgenic Mice Results in Papillary Thyroid Cancers that Undergo Dedifferentiation

2005 • 415 citations

Phase I and Pharmacodynamic Study of the Oral MEK Inhibitor CI-1040 in Patients With Advanced Malignancies

2005 • 400 citations

AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases: mechanism of action in vivo, pharmacokinetic/pharmacodynamic relationship, and potential for combination in preclinical models

2007 • 379 citations

An essential function of the mitogen‐activated protein kinase Erk2 in mouse trophoblast development

2003 • 361 citations

Cytoplasmic Localization of Mitogen-activated Protein Kinase Kinase Directed by Its NH2-terminal, Leucine-rich Short Amino Acid Sequence, Which Acts as a Nuclear Export Signal

1996 • 326 citations

B-Raf Inhibits Programmed Cell Death Downstream of Cytochrome c Release from Mitochondria by Activating the MEK/Erk Pathway

1999 • 311 citations

Therapeutic targeting of the MEK/MAPK signal transduction module in acute myeloid leukemia

2001 • 311 citations

Signaling through the epidermal growth factor receptor during the development of malignancy

2004 • 305 citations

Inhibition of Mitogen-Activated Protein Kinase Kinase Blocks T Cell Proliferation But Does Not Induce or Prevent Anergy

1998 • 298 citations

Raf kinases: Function, regulation and role in human cancer

2007 • 291 citations

Biphasic and synergistic activation of p44mapk (ERK1) by growth factors: correlation between late phase activation and mitogenicity.

1992 • 284 citations

The discovery of the benzhydroxamate MEK inhibitors CI-1040 and PD 0325901

2008 • 268 citations

Deletion of ERK2 Mitogen-Activated Protein Kinase Identifies Its Key Roles in Cortical Neurogenesis and Cognitive Function

2008 • 264 citations

Growth-factor-dependent mitogenesis requires two distinct phases of signalling

2001 • 258 citations

Characterization of insulin-stimulated microtubule-associated protein kinase. Rapid isolation and stabilization of a novel serine/threonine kinase from 3T3-L1 cells.

1988 • 257 citations

Effects of MAP kinase cascade inhibitors on the MKK5/ERK5 pathway

2001 • 253 citations

Continuous ERK Activation Downregulates Antiproliferative Genes throughout G1 Phase to Allow Cell-Cycle Progression

2006 • 252 citations

The Mitogen-Activated Protein/Extracellular Signal-Regulated Kinase Kinase Inhibitor AZD6244 (ARRY-142886) Induces Growth Arrest in Melanoma Cells and Tumor Regression When Combined with Docetaxel

2008 • 240 citations

Constitutively active mutants of MAP kinase kinase (MEK1) induce growth factor-relaxation and oncogenicity when expressed in fibroblasts.

1994 • 222 citations

MEK1-ERK2 Signaling Pathway Protects Myocardium From Ischemic Injury In Vivo

2004 • 219 citations

Rac-PAK Signaling Stimulates Extracellular Signal-Regulated Kinase (ERK) Activation by Regulating Formation of MEK1-ERK Complexes

2002 • 219 citations

Overexpression of mitogen-activated protein kinase kinase (MAPKK) and its mutants in NIH 3T3 cells. Evidence that MAPKK involvement in cellular proliferation is regulated by phosphorylation of serine residues in its kinase subdomains VII and VIII.

1994 • 218 citations

Novel MEK1 Mutation Identified by Mutational Analysis of Epidermal Growth Factor Receptor Signaling Pathway Genes in Lung Adenocarcinoma

2008 • 208 citations

SEK1 deficiency reveals mitogen-activated protein kinase cascade crossregulation and leads to abnormal hepatogenesis

1998 • 196 citations

Single and Combined Silencing of ERK1 and ERK2 Reveals Their Positive Contribution to Growth Signaling Depending on Their Expression Levels

2007 • 195 citations

The p42/p44 MAP Kinase Pathway Prevents Apoptosis Induced by Anchorage and Serum Removal

2000 • 179 citations

Mutations in BRAF and KRAS Converge on Activation of the Mitogen-Activated Protein Kinase Pathway in Lung Cancer Mouse Models

2007 • 174 citations

Clinical experience of MEK inhibitors in cancer therapy

2006 • 173 citations

RDEA119/BAY 869766: A Potent, Selective, Allosteric Inhibitor of MEK1/2 for the Treatment of Cancer

2009 • 173 citations

Inhibition of Growth Factor-induced Protein Synthesis by a Selective MEK Inhibitor in Aortic Smooth Muscle Cells

1996 • 170 citations

The Erk2 MAPK Regulates CD8 T Cell Proliferation and Survival

2008 • 168 citations

A Mek1–Mek2 heterodimer determines the strength and duration of the Erk signal

2009 • 164 citations

Interaction with MEK Causes Nuclear Export and Downregulation of Peroxisome Proliferator-Activated Receptor γ

2006 • 162 citations

The MAP kinase pathway is required for entry into mitosis and cell survival

2004 • 156 citations

Melanocytic nevus-like hyperplasia and melanoma in transgenic BRAFV600E mice

2009 • 152 citations

Targeted inhibition of the extracellular signal-regulated kinase kinase pathway with AZD6244 (ARRY-142886) in the treatment of hepatocellular carcinoma

2007 • 146 citations

Mek1/2 MAPK Kinases Are Essential for Mammalian Development, Homeostasis, and Raf-Induced Hyperplasia

2007 • 139 citations

Treatment of metastatic melanoma with an orally available inhibitor of the Ras-Raf-MAPK cascade.

2003 • 132 citations

AZD6244 (ARRY-142886) vs temozolomide (TMZ) in patients (pts) with advanced melanoma: An open-label, randomized, multicenter, phase II study

2008 • 131 citations

Biphasic and synergistic activation of p44mapk (ERK1) by growth factors: correlation between late phase activation and mitogenicity

1992 • 121 citations

Selective Activation of MEK1 but Not MEK2 by A-Raf from Epidermal Growth Factor-stimulated Hela Cells

1996 • 120 citations

ERK2 but not ERK1 plays a key role in hepatocyte replication: An RNAi-mediated ERK2 knockdown approach in wild-type and ERK1 null hepatocytes

2007 • 103 citations

A phase 1–2 clinical study of a second generation oral MEK inhibitor, PD 0325901 in patients with advanced cancer

2005 • 91 citations

Expression of Activated MEK1 in Differentiating Epidermal Cells Is Sufficient to Generate Hyperproliferative and Inflammatory Skin Lesions

2004 • 87 citations

Extracellular Signal-Regulated Kinase 2-Dependent Phosphorylation Induces Cytoplasmic Localization and Degradation of p21^Cip1

2009 • 77 citations

Mek1 Alters Epidermal Growth and Differentiation

2004 • 73 citations

MEK1 signaling mediates transformation and metastasis of EpH4 mammary epithelial cells independent of an epithelial to mesenchymal transition.

2002 • 67 citations

Activation of MEK1 or MEK2 isoform is sufficient to fully transform intestinal epithelial cells and induce the formation of metastatic tumors

2008 • 66 citations

Ro 09-2210 Exhibits Potent Anti-proliferative Effects on Activated T Cells by Selectively Blocking MKK Activity

1998 • 52 citations

BRAF Activation Initiates but Does Not Maintain Invasive Prostate Adenocarcinoma

2008 • 49 citations

Use of mitogenic cascade blockers for treatment of C-Raf induced lung adenoma in vivo: CI-1040 strongly reduces growth and improves lung structure

2004 • 49 citations

Differential Regulation of Mitogen-Activated Protein/ERK Kinase (MEK)1 and MEK2 and Activation by a Ras-Independent Mechanism

1997 • 48 citations

Characterization of a Novel Mitogen-Activated Protein Kinase Kinase 1/2 Inhibitor with a Unique Mechanism of Action for Cancer Therapy

2009 • 31 citations

A phase II study of AZD6244 in advanced or metastatic hepatocellular carcinoma

2009 • 31 citations

Pharmacokinetics (PK) and pharmacodynamics (PD) of PD 0325901, a second generation MEK inhibitor after multiple oral doses of PD 0325901 to advanced cancer patients

2005 • 28 citations

Efficacy and safety of AZD6244 (ARRY-142886) as second/third-line treatment of patients (pts) with advanced non-small cell lung cancer (NSCLC)

2008 • 28 citations

Preclinical In vivo Evaluation of Efficacy, Pharmacokinetics, and Pharmacodynamics of a Novel MEK1/2 Kinase Inhibitor RO5068760 in Multiple Tumor Models

2010 • 28 citations

Mek1/2 gene dosage determines tissue response to oncogenic Ras signaling in the skin

2009 • 25 citations

AZD6244 (ARRY-142886) versus capecitabine (CAP) in patients (pts) with metastatic colorectal cancer (mCRC) who have failed prior chemotherapy

2008 • 19 citations

A phase 1 dose-escalation study of XL518, a potent MEK inhibitor administered orally daily to subjects with solid tumors

2008 • 17 citations

Clinical aspects of a phase I study of PD-0325901, a selective oral MEK inhibitor, in patients with advanced cancer

2007 • 16 citations

XL518, a potent selective orally bioavailable MEK1 inhibitor, downregulates the RAS/RAF/MEK/ERK pathway in vivo, resulting in tumor growth inhibition and regression in pre-clinical models

2007 • 13 citations

A three-part, phase I, dose-escalation study of GSK1120212, a potent MEK inhibitor, administered orally to subjects with solid tumors or lymphoma

2009 • 13 citations