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

Olga K. Mirzoeva, Debopriya Das, Laura M. Heiser, Sanchita Bhattacharya, Doris Siwak, Rina Gendelman, Nora Bayani, Nicholas J. Wang, Richard M. Neve, Yinghui Guan, Zhi Hu, Zachary Knight, Heidi S. Feiler, Philippe Gascard, Bahram Parvin, Paul T. Spellman, Kevan M. Shokat, Andrew J. Wyrobek, Mina J. Bissell, Frank McCormickWen Lin Kuo, Gordon B. Mills, Joe W. Gray, W. Michael Korn

Research output: Contribution to journalArticle

274 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)565-572
Number of pages8
JournalCancer Research
Volume69
Issue number2
DOIs
StatePublished - Jan 15 2009

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Mirzoeva, O. K., Das, D., Heiser, L. M., Bhattacharya, S., Siwak, D., Gendelman, R., Bayani, N., Wang, N. J., Neve, R. M., Guan, Y., Hu, Z., Knight, Z., Feiler, H. S., Gascard, P., Parvin, B., Spellman, P. T., Shokat, K. M., Wyrobek, A. J., Bissell, M. J., ... Korn, W. M. (2009). Basal subtype and MAPK/ERK kinase (MEK)-phosphoinositide 3-kinase feedback signaling determine susceptibility of breast cancer cells to MEK inhibition. Cancer Research, 69(2), 565-572. https://doi.org/10.1158/0008-5472.CAN-08-3389