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

Research output: Contribution to journalArticle

269 Citations (Scopus)

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
Externally publishedYes

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1-Phosphatidylinositol 4-Kinase
Mitogen-Activated Protein Kinase Kinases
Extracellular Signal-Regulated MAP Kinases
Phosphotransferases
Breast Neoplasms
Phosphatidylinositol 3-Kinase
Basal Cell Neoplasms
Apoptosis
MAP Kinase Kinase Kinases
Cytoprotection
Cell Cycle Checkpoints
Mitogen-Activated Protein Kinases
Epidermal Growth Factor Receptor
Patient Selection
Signal Transduction
Clinical Trials
Cell Line
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Basal subtype and MAPK/ERK kinase (MEK)-phosphoinositide 3-kinase feedback signaling determine susceptibility of breast cancer cells to MEK inhibition. / Mirzoeva, Olga K.; Das, Debopriya; Heiser, Laura; Bhattacharya, Sanchita; Siwak, Doris; Gendelman, Rina; Bayani, Nora; Wang, Nicholas J.; Neve, Richard M.; Guan, Yinghui; Hu, Zhi; Knight, Zachary; Feiler, Heidi; Gascard, Philippe; Parvin, Bahram; Spellman, Paul; Shokat, Kevan M.; Wyrobek, Andrew J.; Bissell, Mina J.; McCormick, Frank; Kuo, Wen Lin; Mills, Gordon; Gray, Joe; Korn, W. Michael.

In: Cancer Research, Vol. 69, No. 2, 15.01.2009, p. 565-572.

Research output: Contribution to journalArticle

Mirzoeva, OK, Das, D, Heiser, L, Bhattacharya, S, Siwak, D, Gendelman, R, Bayani, N, Wang, NJ, Neve, RM, Guan, Y, Hu, Z, Knight, Z, Feiler, H, Gascard, P, Parvin, B, Spellman, P, Shokat, KM, Wyrobek, AJ, Bissell, MJ, McCormick, F, Kuo, WL, Mills, G, Gray, J & Korn, WM 2009, 'Basal subtype and MAPK/ERK kinase (MEK)-phosphoinositide 3-kinase feedback signaling determine susceptibility of breast cancer cells to MEK inhibition', Cancer Research, vol. 69, no. 2, pp. 565-572. https://doi.org/10.1158/0008-5472.CAN-08-3389
Mirzoeva, Olga K. ; Das, Debopriya ; Heiser, Laura ; Bhattacharya, Sanchita ; Siwak, Doris ; Gendelman, Rina ; Bayani, Nora ; Wang, Nicholas J. ; Neve, Richard M. ; Guan, Yinghui ; Hu, Zhi ; Knight, Zachary ; Feiler, Heidi ; Gascard, Philippe ; Parvin, Bahram ; Spellman, Paul ; Shokat, Kevan M. ; Wyrobek, Andrew J. ; Bissell, Mina J. ; McCormick, Frank ; Kuo, Wen Lin ; Mills, Gordon ; Gray, Joe ; Korn, W. Michael. / Basal subtype and MAPK/ERK kinase (MEK)-phosphoinositide 3-kinase feedback signaling determine susceptibility of breast cancer cells to MEK inhibition. In: Cancer Research. 2009 ; Vol. 69, No. 2. pp. 565-572.
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AU - Bhattacharya, Sanchita

AU - Siwak, Doris

AU - Gendelman, Rina

AU - Bayani, Nora

AU - Wang, Nicholas J.

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AU - Guan, Yinghui

AU - Hu, Zhi

AU - Knight, Zachary

AU - Feiler, Heidi

AU - Gascard, Philippe

AU - Parvin, Bahram

AU - Spellman, Paul

AU - Shokat, Kevan M.

AU - Wyrobek, Andrew J.

AU - Bissell, Mina J.

AU - McCormick, Frank

AU - Kuo, Wen Lin

AU - Mills, Gordon

AU - Gray, Joe

AU - Korn, W. Michael

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