Abstract：
:Specific inhibitors of mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK) have been developed that efficiently inhibit the oncogenic RAF-MEK-ERK pathway. We used a systems-based approach to identify breast cancer subtypes particularly susceptible to MEK inhibitors and to understand molecular mechanisms conferring resistance to such compounds. Basal-type breast cancer cells were found to be particularly susceptible to growth inhibition by small-molecule MEK inhibitors. Activation of the phosphatidylinositol 3-kinase (PI3K) pathway in response to MEK inhibition through a negative MEK-epidermal growth factor receptor-PI3K feedback loop was found to limit efficacy. Interruption of this feedback mechanism by targeting MEK and PI3K produced synergistic effects, including induction of apoptosis and, in some cell lines, cell cycle arrest and protection from apoptosis induced by proapoptotic agents. These findings enhance our understanding of the interconnectivity of oncogenic signal transduction circuits and have implications for the design of future clinical trials of MEK inhibitors in breast cancer by guiding patient selection and suggesting rational combination therapies.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Mirzoeva OK,Das D,Heiser LM,Bhattacharya S,Siwak D,Gendelman R,Bayani N,Wang NJ,Neve RM,Guan Y,Hu Z,Knight Z,Feiler HS,Gascard P,Parvin B,Spellman PT,Shokat KM,Wyrobek AJ,Bissell MJ,McCormick F,Kuo WL,Mills GB,doi
10.1158/0008-5472.CAN-08-3389subject
Has Abstractpub_date
2009-01-15 00:00:00pages
565-72issue
2eissn
0008-5472issn
1538-7445pii
69/2/565journal_volume
69pub_type
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