Format

Send to

Choose Destination
Pharmacol Ther. 2014 Feb;141(2):160-71. doi: 10.1016/j.pharmthera.2013.10.001. Epub 2013 Oct 9.

MEK in cancer and cancer therapy.

Author information

1
INSERM U728 and Department of Medical Oncology, Beaujon University Hospital, AP-HP-PRES, Paris 7 Diderot, 100 boulevard du Général Leclerc, 92110 Clichy, France; Department of Gastroenterology and Pancreatology, Beaujon University Hospital, AP-HP-PRES, Paris 7 Diderot, 100 boulevard du Général Leclerc, 92110 Clichy, France.
2
AAREC Filia Research, 1 place Paul Verlaine, 92100 Boulogne-Billancourt, France.
3
INSERM U728 and Department of Medical Oncology, Beaujon University Hospital, AP-HP-PRES, Paris 7 Diderot, 100 boulevard du Général Leclerc, 92110 Clichy, France.
4
Department of Pathology, Beaujon University Hospital, AP-HP-PRES, Paris 7 Diderot, 100 boulevard du Général Leclerc, 92110 Clichy, France.
5
INSERM U728 and Department of Medical Oncology, Beaujon University Hospital, AP-HP-PRES, Paris 7 Diderot, 100 boulevard du Général Leclerc, 92110 Clichy, France. Electronic address: eric.raymond@bjn.aphp.fr.

Abstract

The mitogen-activated extracellular signal-regulated kinase (MEK) pathway is one of the best-characterized kinase cascades in cancer cell biology. It is triggered by either growth factors or activating mutations of major oncogenic proteins in this pathway, the most common being Ras and Raf. Deregulation of this pathway is frequently observed and plays a central role in the carcinogenesis and maintenance of several cancers, including melanoma, pancreatic, lung, colorectal, and breast cancers. Targeting these kinases offers promise of novel therapies. MEK inhibitors (MEKi) are currently under evaluation in clinical trials and many have shown activity. In this review, we comprehensively examine the role of the MEK pathway in carcinogenesis and its therapeutic potential in cancer patients, with a focus on MEKi. We describe the clinical perspectives of MEKi in the two main models of Ras-ERK driven tumors, BRAF-mutant ("addicted" to the pathway) and KRAS-mutant (non-"addicted"). We also highlight the known mechanisms of resistance to MEKi and emerging strategies to overcome it.

KEYWORDS:

CRC; Combination; EMT; ERK; ERK inhibitors; GAP; GEF; GTPase-activating protein; HCC; HR; MAP kinase; MAP kinases; MAPK; MEK; MEK inhibitor; MEKi; NSCLC; PAC; PFS; PanIN; Predictive biomarker; Resistance; TKR; Targeted therapy; colorectal cancer; epithelial-to-mesenchymal transition; extracellular signal-regulated kinase; guanine nucleotide exchange factor; hazard ratio; hepatocellular carcinoma; mitogen-activated extracellular signal-regulated kinase; non-small cell lung carcinoma; pRb; pancreatic adenocarcinoma; pancreatic intraepithelial neoplasia; progression-free survival; retinoblastoma protein; tyrosine kinase receptor

[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center