From Basic Research to Clinical Development of MEK1/2 Inhibitors for Cancer Therapy

Overview

Journal J Hematol Oncol

Publisher Biomed Central

Specialties Hematology
Oncology

Date 2010 Feb 13

PMID 20149254

Citations 110

Authors

Christophe Fremin

Sylvain Meloche

Affiliations

Soon will be listed here.

Abstract

The Ras-dependent Raf/MEK/ERK1/2 mitogen-activated protein (MAP) kinase signaling pathway is a major regulator of cell proliferation and survival. Not surprisingly, hyperactivation of this pathway is frequently observed in human malignancies as a result of aberrant activation of receptor tyrosine kinases or gain-of-function mutations in RAS or RAF genes. Components of the ERK1/2 pathway are therefore viewed as attractive candidates for the development of targeted therapies of cancer. In this article, we briefly review the basic research that has laid the groundwork for the clinical development of small molecules inhibitors of the ERK1/2 pathway. We then present the current state of clinical evaluation of MEK1/2 inhibitors in cancer and discuss challenges ahead.

Citing Articles

[Bilateral, central serous chorioretinopathy under BRAF(B-rapidly accelerated fibrosarcoma)-/MEK (mitogen-activated protein kinase kinase)-inhibitor therapy in metastatic cutaneous melanoma.].

Rastoaca C, Berger T, Seitz B, Abdin A Ophthalmologie. 2024; 122(1):52-57.

PMID: 39643749 DOI: 10.1007/s00347-024-02140-3.

Molecular Dynamics Simulation on the Suppression Mechanism of Phosphorylation to Ser222 by Allosteric Inhibitors Targeting MEK1/2 Kinase.

Mudedla S, Lee H, Kim J, Jang S, Doddareddy M, Sanam S ACS Omega. 2024; 9(29):31946-31956.

PMID: 39072081 PMC: 11270731. DOI: 10.1021/acsomega.4c03615.

Molecular Targeting of the Phosphoinositide-3-Protein Kinase (PI3K) Pathway across Various Cancers.

Shan K, Bonano-Rios A, Theik N, Hussein A, Blaya M Int J Mol Sci. 2024; 25(4).

PMID: 38396649 PMC: 10888452. DOI: 10.3390/ijms25041973.

Neuronal differentiation drives the antitumor activity of mitogen-activated protein kinase kinase (MEK) inhibition in glioblastoma.

Khan S, Martinez-Ledesma E, Dong J, Mahalingam R, Park S, Piao Y Neurooncol Adv. 2023; 5(1):vdad132.

PMID: 38130900 PMC: 10734674. DOI: 10.1093/noajnl/vdad132.

Synergistic anticancer effect by targeting CDK2 and EGFR-ERK signaling.

Wu J, Chen Y, Li R, Guan Y, Chen M, Yin H J Cell Biol. 2023; 223(1).

PMID: 37955924 PMC: 10641568. DOI: 10.1083/jcb.202203005.

References

Dudley D, Pang L, Decker S, Bridges A, Saltiel A . A synthetic inhibitor of the mitogen-activated protein kinase cascade. Proc Natl Acad Sci U S A. 1995; 92(17):7686-9. PMC: 41210. DOI: 10.1073/pnas.92.17.7686. View

Hynes N, Lane H . ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer. 2005; 5(5):341-54. DOI: 10.1038/nrc1609. View

Pearson G, Robinson F, Beers Gibson T, Xu B, Karandikar M, Berman K . Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev. 2001; 22(2):153-83. DOI: 10.1210/edrv.22.2.0428. View

Cowley S, PATERSON H, Kemp P, Marshall C . Activation of MAP kinase kinase is necessary and sufficient for PC12 differentiation and for transformation of NIH 3T3 cells. Cell. 1994; 77(6):841-52. DOI: 10.1016/0092-8674(94)90133-3. View

Garnett M, Marais R . Guilty as charged: B-RAF is a human oncogene. Cancer Cell. 2004; 6(4):313-9. DOI: 10.1016/j.ccr.2004.09.022. View

Pages G, Guerin S, Grall D, Bonino F, Smith A, Anjuere F . Defective thymocyte maturation in p44 MAP kinase (Erk 1) knockout mice. Science. 1999; 286(5443):1374-7. DOI: 10.1126/science.286.5443.1374. View

Solit D, Garraway L, Pratilas C, Sawai A, Getz G, Basso A . BRAF mutation predicts sensitivity to MEK inhibition. Nature. 2005; 439(7074):358-62. PMC: 3306236. DOI: 10.1038/nature04304. View

Grandis J, Sok J . Signaling through the epidermal growth factor receptor during the development of malignancy. Pharmacol Ther. 2004; 102(1):37-46. DOI: 10.1016/j.pharmthera.2004.01.002. View

Kamakura S, Moriguchi T, Nishida E . Activation of the protein kinase ERK5/BMK1 by receptor tyrosine kinases. Identification and characterization of a signaling pathway to the nucleus. J Biol Chem. 1999; 274(37):26563-71. DOI: 10.1074/jbc.274.37.26563. View

10.

Wilhelm S, Carter C, Lynch M, Lowinger T, Dumas J, Smith R . Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov. 2006; 5(10):835-44. DOI: 10.1038/nrd2130. View

11.

Meloche S, Pouyssegur J . The ERK1/2 mitogen-activated protein kinase pathway as a master regulator of the G1- to S-phase transition. Oncogene. 2007; 26(22):3227-39. DOI: 10.1038/sj.onc.1210414. View

12.

Scholl F, Dumesic P, Barragan D, Charron J, Khavari P . Mek1/2 gene dosage determines tissue response to oncogenic Ras signaling in the skin. Oncogene. 2009; 28(12):1485-95. PMC: 3084589. DOI: 10.1038/onc.2008.459. View

13.

Sebolt-Leopold J, Herrera R . Targeting the mitogen-activated protein kinase cascade to treat cancer. Nat Rev Cancer. 2004; 4(12):937-47. DOI: 10.1038/nrc1503. View

14.

Mody N, Leitch J, Armstrong C, DIXON J, Cohen P . Effects of MAP kinase cascade inhibitors on the MKK5/ERK5 pathway. FEBS Lett. 2001; 502(1-2):21-4. DOI: 10.1016/s0014-5793(01)02651-5. View

15.

Ohren J, Chen H, Pavlovsky A, Whitehead C, Zhang E, Kuffa P . Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition. Nat Struct Mol Biol. 2004; 11(12):1192-7. DOI: 10.1038/nsmb859. View

16.

Hwang C, Lee C, Kwon K . Extracellular signal-regulated kinase 2-dependent phosphorylation induces cytoplasmic localization and degradation of p21Cip1. Mol Cell Biol. 2009; 29(12):3379-89. PMC: 2698740. DOI: 10.1128/MCB.01758-08. View

17.

Lavoie J, LAllemain G, Brunet A, Muller R, Pouyssegur J . Cyclin D1 expression is regulated positively by the p42/p44MAPK and negatively by the p38/HOGMAPK pathway. J Biol Chem. 1996; 271(34):20608-16. DOI: 10.1074/jbc.271.34.20608. View

18.

Haass N, Sproesser K, Nguyen T, Contractor R, Medina C, Nathanson K . 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. Clin Cancer Res. 2008; 14(1):230-9. DOI: 10.1158/1078-0432.CCR-07-1440. View

19.

Fukuda M, Gotoh I, Gotoh Y, Nishida E . 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. J Biol Chem. 1996; 271(33):20024-8. DOI: 10.1074/jbc.271.33.20024. View

20.

Favata M, Horiuchi K, Manos E, Daulerio A, Stradley D, Feeser W . Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J Biol Chem. 1998; 273(29):18623-32. DOI: 10.1074/jbc.273.29.18623. View