Molecular pathways: Mitogen-activated protein kinase pathway mutations and drug resistance

Pritchard, A.L. and Hayward, N.K. (2013) Molecular pathways: Mitogen-activated protein kinase pathway mutations and drug resistance. Clinical Cancer Research, 19 9: 2301-2309. doi:10.1158/1078-0432.CCR-12-0383

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Author Pritchard, A.L.
Hayward, N.K.
Title Molecular pathways: Mitogen-activated protein kinase pathway mutations and drug resistance
Journal name Clinical Cancer Research   Check publisher's open access policy
ISSN 1078-0432
Publication date 2013-05-01
Sub-type Article (original research)
DOI 10.1158/1078-0432.CCR-12-0383
Open Access Status
Volume 19
Issue 9
Start page 2301
End page 2309
Total pages 9
Place of publication Philadelphia, PA, U.S.A.
Publisher American Association for Cancer Research
Collection year 2014
Language eng
Subject 1306 Cancer Research
2730 Oncology
Abstract Receptor tyrosine kinases are a diverse family of transmembrane proteins that can activate multiple pathways upon ligation of the receptor, one of which is the series of mitogen-activated protein kinase (MAPK) signaling cascades. The MAPK pathways play critical roles in a wide variety of cancer types, from hematologic malignancies to solid tumors. Aberrations include altered expression levels and activation states of pathway components, which can sometimes be attributable to mutations in individual members. The V600E mutation of BRAF was initially described in 2002 and has been found at particularly high frequency in melanoma and certain subtypes of colorectal cancer. In the relatively short time since this discovery, a family of drugs has been developed that specifically target this mutated BRAF isoform, which, after results from phase I/II and III clinical trials, was granted U.S. Food and Drug Administration approval in August 2011. Although these drugs produce clinically meaningful increases in progression-free and overall survival, due to acquired resistance they have not improved mortality rates. New drugs targeting other members of the MAPK pathways are in clinical trials or advanced stages of development. It is hoped that combination therapies of these new drugs in conjunction with BRAF inhibitors will counteract the mechanisms of resistance and provide cures. The clinical implementation of next-generation sequencing is leading to a greater understanding of the genetic architecture of tumors, along with acquired mechanisms of drug resistance, which will guide the development of tumor-specific inhibitors and combination therapies in the future.
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Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
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