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HERO ID
8343664
Reference Type
Journal Article
Title
PI3K and MEK inhibitor combinations: Examining the evidence in selected tumor types
Author(s)
Britten, CD
Year
2013
Is Peer Reviewed?
Yes
Journal
Cancer Chemotherapy and Pharmacology
ISSN:
0344-5704
EISSN:
1432-0843
Volume
71
Issue
6
Page Numbers
1395-1409
Language
English
DOI
10.1007/s00280-013-2121-1
Abstract
The PI3K/AKT/mTOR and RAS/RAF/MEK/ERK pathways are two of the most frequently dysregulated kinase cascades in human cancer. Molecular alterations in these pathways are implicated in tumorigenesis and resistance to anticancer therapies. The PI3K/AKT/mTOR and RAS/RAF/MEK/ERK pathways are known to interact with each other at several nodes, and mounting evidence suggests that dual blockade of both pathways may be required to achieve anticancer effects in certain contexts. This may include tumor types with a high frequency of RAS/RAF/MEK/ERK pathway activation, or situations in which dual pathway strategies may be required to overcome resistance to current targeted therapies. Several clinical studies are currently evaluating the combination of PI3K and MEK inhibitors in a variety of different cancers with certain types of molecular alterations. This review will summarize existing knowledge of the PI3K/AKT/mTOR and RAS/RAF/MEK/ERK pathways, the cross-talk between them, and the current generation of PI3K and MEK inhibitors that target them. The preclinical rationale for dual pathway inhibition will be discussed within the context of the major tumor types currently being explored in ongoing clinical trials, namely malignant melanoma with BRAF or NRAS mutations, and colorectal, ovarian, pancreatic, and basal-like breast cancers. The emerging clinical profile of PI3K and MEK inhibitor combinations, as reported in Phase I trials, will also be discussed. © 2013 Springer-Verlag Berlin Heidelberg.
Keywords
BRAF mutation; MEK inhibitor; NRAS mutation; PI3K inhibitor; PI3K/AKT/mTOR pathway; RAS/RAF/MEK/ERK pathway
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