Feedback Mechanisms Promote Cooperativity for Small Molecule Inhibitors of Epidermal and Insulin-Like Growth Factor Receptors
| Autor: | Mark J. Mulvihill, Kenneth K. Iwata, Stuart Thomson, Yan Yao, Qun-Sheng Ji, Sharon Barr, Elizabeth Buck, David Epstein, John D. Haley, Jonathan A. Pachter, Alexandra Eyzaguirre, Eric J. Brown, Mathew O'Connor, Maryland Rosenfeld-Franklin, Mark Miglarese, Neil W. Gibson |
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| Rok vydání: | 2008 |
| Předmět: |
MAPK/ERK pathway
Cancer Research MAP Kinase Signaling System Mice Nude Antineoplastic Agents Apoptosis Biology Receptor IGF Type 1 Erlotinib Hydrochloride Mice Growth factor receptor Cell Line Tumor Animals Humans ERBB3 Growth factor receptor inhibitor Epidermal growth factor receptor Phosphorylation Protein kinase B PI3K/AKT/mTOR pathway Adaptor Proteins Signal Transducing Insulin-like growth factor 1 receptor Feedback Physiological Dose-Response Relationship Drug Imidazoles Drug Synergism Neoplasms Experimental Cell biology ErbB Receptors Oncology Pyrazines Insulin Receptor Substrate Proteins Quinazolines biology.protein Female Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | Cancer Research. 68:8322-8332 |
| ISSN: | 1538-7445 0008-5472 |
| Popis: | Epidermal growth factor receptor (EGFR) and insulin-like growth factor-I receptor (IGF-IR) can cooperate to regulate tumor growth and survival, and synergistic growth inhibition has been reported for combined blockade of EGFR and IGF-IR. However, in preclinical models, only a subset of tumors exhibit high sensitivity to this combination, highlighting the potential need for patient selection to optimize clinical efficacy. Herein, we have characterized the molecular basis for cooperative growth inhibition upon dual EGFR and IGF-IR blockade and provide biomarkers that seem to differentiate response. We find for epithelial, but not for mesenchymal-like, tumor cells that Akt is controlled cooperatively by EGFR and IGF-IR. This correlates with synergistic apoptosis and growth inhibition in vitro and growth regression in vivo upon combined blockade of both receptors. We identified two molecular aspects contributing to synergy: (a) inhibition of EGFR or IGF-IR individually promotes activation of the reciprocal receptor; (b) inhibition of EGFR-directed mitogen-activated protein kinase (MAPK) shifts regulation of Akt from EGFR toward IGF-IR. Targeting the MAPK pathway through downstream MAPK/extracellular signal-regulated kinase kinase (MEK) antagonism similarly promoted IGF-driven pAkt and synergism with IGF-IR inhibition. Mechanistically, we find that inhibition of the MAPK pathway circumvents a negative feedback loop imposed on the IGF-IR– insulin receptor substrate 1 (IRS-1) signaling complex, a molecular scenario that parallels the negative feedback loop between mTOR-p70S6K and IRS-1 that mediates rapamycin-directed IGF-IR signaling. Collectively, these data show that resistance to inhibition of MEK, mTOR, and EGFR is associated with enhanced IGF-IR–directed Akt signaling, where all affect feedback loops converging at the level of IRS-1. [Cancer Res 2008;68(20):8322–32] |
| Databáze: | OpenAIRE |
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