Feedback mechanisms promote cooperativity for small molecule inhibitors of epidermal and insulin-like growth factor receptors.

摘要: Epidermal growth factor receptor (EGFR) and insulin-like factor-I (IGF-IR) can cooperate to regulate tumor survival, synergistic inhibition has been reported for combined blockade of EGFR IGF-IR. However, in preclinical models, only a subset tumors exhibit high sensitivity this combination, highlighting the potential need patient selection optimize clinical efficacy. Herein, we have characterized molecular basis cooperative upon dual IGF-IR provide biomarkers that seem differentiate response. We find epithelial, but not mesenchymal-like, cells Akt is controlled cooperatively by This correlates with apoptosis vitro regression vivo both receptors. identified two aspects contributing synergy: (a) or individually promotes activation reciprocal receptor; (b) EGFR-directed mitogen-activated protein kinase (MAPK) shifts regulation from toward Targeting MAPK pathway through downstream MAPK/extracellular signal-regulated (MEK) antagonism similarly promoted IGF-driven pAkt synergism inhibition. Mechanistically, circumvents negative feedback loop imposed on IGF-IR- insulin substrate 1 (IRS-1) signaling complex, scenario parallels between mTOR-p70S6K IRS-1 mediates rapamycin-directed signaling. Collectively, these data show resistance MEK, mTOR, associated enhanced IGF-IR-directed signaling, where all affect loops converging at level IRS-1.