Basal subtype and MAPK/ERK kinase (MEK)-phosphoinositide 3-kinase feedback signaling determine susceptibility of breast cancer cells to MEK inhibition.

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 Res

journal_title

Cancer research

authors

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-08-3389

subject

Has Abstract

pub_date

2009-01-15 00:00:00

pages

565-72

issue

2

eissn

0008-5472

issn

1538-7445

pii

69/2/565

journal_volume

69

pub_type

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