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Abstract
The extracellular signal‐regulated kinase (ERK) signaling pathway is a major determinant in the control of diverse cellular processes such as proliferation, survival, differentiation and motility. This pathway is often up‐regulated in human tumors and as such represents an attractive target for the development of anticancer drugs. Because of its multiple roles in the acquisition of a complex malignant phenotype, specific blockade of the ERK pathway is expected to result in not only an anti‐proliferative effect but also in anti‐metastatic and anti‐angiogenic effects in tumor cells. Recently potent small‐molecule inhibitors targeting the components of the ERK pathway have been developed. Among them, BAY 43‐9006 (Raf inhibitor), and PD184352, PD0325901 and ARRY‐142886 (MEK1/2 inhibitors) have reached the clinical trial stage. We briefly discuss the possibility that combination of ERK pathway inhibitors (cytostatic agents) and conventional anticancer drugs (cytotoxic agents) provides an excellent basis for the development of new chemotherapeutic strategies against cancer.
| Abbreviations | ||
| ATF2 | = | activating transcription factor 2 |
| Bad | = | bcl‐2 associated death promoter |
| Bcl‐2 | = | B cell leukemia‐2 |
| Bim | = | bcl‐2 interacting mediator of cell death |
| CAS | = | Crk‐associated substrate |
| Crk | = | CT10 regulator of kinase |
| ECM | = | extracellular matrix |
| EGFR | = | epidermal growth factor receptor |
| ERK1/2 | = | extracellular signal‐regulated kinase 1/2 |
| FAK | = | focal adhesion kinase |
| FGFR | = | fibroblast growth factor receptor |
| Grb2 | = | growth factor receptor‐bound protein 2 |
| HIF‐1α | = | hypoxia inducible factor‐1α |
| MAP2/4 | = | microtubule associated protein 2/4 |
| MAPK | = | mitogen‐activated protein kinase |
| MAPKK | = | MAPK kinase |
| MAPKKK | = | MAPKK kinase |
| MEK1/2 | = | MAP kinase/ERK kinase 1/2 |
| MEKK | = | MEK kinase |
| MLCK | = | myosin light chain kinase |
| MNK1/2 | = | MAP kinase interacting kinase 1/2 |
| PDGFR | = | platelet derived growth factor receptor |
| PKC | = | protein kinase C |
| PLC‐γ | = | phospholipase C‐γ |
| Rsk | = | ribosomal S6 kinase |
| RTK | = | receptor tyrosine kinase |
| Shc | = | src homologous and collagen |
| SOS | = | son of sevenless |
| Stat | = | signal transducers and activators of transcription |
| VEGFR | = | vascular endothelial growth factor receptor |
| Abbreviations | ||
| ATF2 | = | activating transcription factor 2 |
| Bad | = | bcl‐2 associated death promoter |
| Bcl‐2 | = | B cell leukemia‐2 |
| Bim | = | bcl‐2 interacting mediator of cell death |
| CAS | = | Crk‐associated substrate |
| Crk | = | CT10 regulator of kinase |
| ECM | = | extracellular matrix |
| EGFR | = | epidermal growth factor receptor |
| ERK1/2 | = | extracellular signal‐regulated kinase 1/2 |
| FAK | = | focal adhesion kinase |
| FGFR | = | fibroblast growth factor receptor |
| Grb2 | = | growth factor receptor‐bound protein 2 |
| HIF‐1α | = | hypoxia inducible factor‐1α |
| MAP2/4 | = | microtubule associated protein 2/4 |
| MAPK | = | mitogen‐activated protein kinase |
| MAPKK | = | MAPK kinase |
| MAPKKK | = | MAPKK kinase |
| MEK1/2 | = | MAP kinase/ERK kinase 1/2 |
| MEKK | = | MEK kinase |
| MLCK | = | myosin light chain kinase |
| MNK1/2 | = | MAP kinase interacting kinase 1/2 |
| PDGFR | = | platelet derived growth factor receptor |
| PKC | = | protein kinase C |
| PLC‐γ | = | phospholipase C‐γ |
| Rsk | = | ribosomal S6 kinase |
| RTK | = | receptor tyrosine kinase |
| Shc | = | src homologous and collagen |
| SOS | = | son of sevenless |
| Stat | = | signal transducers and activators of transcription |
| VEGFR | = | vascular endothelial growth factor receptor |
Acknowledgements
We would like to thank Dr Christiane Brahimi‐Horn for critical reading of the manuscript, and all the colleagues in our laboratories for helpful discussion. This work was supported in part by Grants‐in‐aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MK), and from the CNRS, the French Ministry of Education and Research, the Agency for Cancer Research (JP).