Stromal cell-derived factor 1α mediates resistance to mTOR-directed therapy in pancreatic cancer

Colin D. Weekes, Dongweon Song, John Arcaroli, Lora A. Wilson, Belen Rubio-Viqueira, George Cusatis, Elizabeth Garrett-Mayer, Wells A. Messersmith, Robert A. Winn, Manuel Hidalgo

Research output: Contribution to journalArticle

Abstract

PURPOSE: The factors preventing the translation of preclinical findings supporting the clinical development mTOR-targeted therapy in pancreatic cancer therapy remain undetermined. Stromal cell-derived factor 1α (SDF-1α)-CXCR4 signaling was examined as a representative microenvironmental factor able to promote mTOR-targeted therapy resistance in pancreatic cancer. EXPERIMENTAL DESIGN: Primary pancreas explant xenografts and in vitro experiments were used to perform pharmacodynamic analyses of SDF-1α-CXCR4 regulation of the mTOR pathway. Combinatorial effects of CXCR4, EGFR, and mTOR pharmacologic inhibition were evaluated in temsirolimus-resistant and -sensitive xeno-grafts. Intratumoral gene and protein expressions of mTOR pathway effectors cyclin D1, c-Myc, and VEGF were evaluated. RESULTS: Baseline intratumoral SDF-1α gene expression correlated with temsirolimus resistance in explant models. SDF-1α stimulation of pancreatic cells resulted in CXCR4-mediated PI3-kinase-dependent S6-RP phosphorylation (pS6-RP) on exposure to temsirolimus. Combinatorial therapy with AMD3465 (CXCR4 small-molecule inhibitor) and temsirolimus resulted in effective tumor growth inhibition to overcome temsirolimus resistance. In contrast, SDF-1α exposure induced a temsirolimus-resistant phenotype in temsirolimus-sensitive explants. AMD3465 inhibited CXCR4-mediated intratumoral S6-RP phosphorylation and cyclin D and c-myc gene expression. Next, CXCR4 promoted intra-tumoral EGFR expression in association with temsirolimus resistance. Treatment with AMD3465, temsirolimus- and erlotinib-mediated tumor growth inhibition to overcome temsirolimus resistance in the explant model. Lastly, SDF-1α- CXCR4 signaling increased intratumoral VEGF gene and protein expression. CONCLUSIONS: SDF-1α-CXCR4 signaling represents a microenvironmental factor that can maintain mTOR pathway fidelity to promote resistance to mTOR-targeted therapy in pancreatic cancer by a variety of mechanisms such as recruitment of EGFR signaling and angiogenesis.

Original languageEnglish (US)
Pages (from-to)690-701
Number of pages12
JournalNeoplasia (United States)
Volume14
Issue number8
DOIs
StatePublished - Aug 2012

ASJC Scopus subject areas

  • Cancer Research

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    Weekes, C. D., Song, D., Arcaroli, J., Wilson, L. A., Rubio-Viqueira, B., Cusatis, G., Garrett-Mayer, E., Messersmith, W. A., Winn, R. A., & Hidalgo, M. (2012). Stromal cell-derived factor 1α mediates resistance to mTOR-directed therapy in pancreatic cancer. Neoplasia (United States), 14(8), 690-701. https://doi.org/10.1593/neo.111810