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Basal Subtype and MAPK/ERK Kinase (MEK)-Phosphoinositide 3-Kinase Feedback Signaling Determine Susceptibility of Breast Cancer Cells to MEK Inhibition

¹ Division of Gastroenterology, Department of Medicine, ² Department of Cellular and Molecular Pharmacology, ³ Helen Diller Family Comprehensive Cancer Center, and ⁴ Divisions of Gastroenterology and Hematology/Oncology, Department of Medicine, University of California, San Francisco, California; ⁵ Lawrence Berkeley National Laboratory, Life Sciences Division, Berkeley, California; and ⁶ Department of Systems Biology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas

Requests for reprints: W. Michael Korn, Divisions of Gastroenterology and Hematology/Oncology, Department of Medicine, University of California, 2340 Sutter Street, San Francisco, CA 94115. Phone: 415-502-2844/415-476-0137; Fax: 415-502-4787; E-mail: mkorn{at}cc.ucsf.edu.

Key Words: breast cancer • mitogen-activated protein kinase kinase • phosphoinositide 3-kinase

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. [Cancer Res 2009;69(2):565–72]

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