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Cancer Res. 2012 Sep 1;72(17):4329-39. doi: 10.1158/0008-5472.CAN-12-0136. Epub 2012 Jul 9.

Global quantitative phosphoproteome analysis of human tumor xenografts treated with a CD44 antagonist.

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1
Discovery Oncology, Pharma Research and Early Development, Roche Diagnostics GmbH, Penzberg, Germany. Stefan.weigand@roche.com

Abstract

The cell surface glycoprotein CD44 plays an important role in the development and progression of various tumor types. RG7356 is a humanized antibody targeting the constant region of CD44 that shows antitumor efficacy in mice implanted with CD44-expressing tumors such as MDA-MB-231 breast cancer cells. CD44 receptor seems to function as the main receptor for hyaluronic acid and osteopontin, serving as coreceptor for growth factor pathways like cMet, EGFR, HER-2, and VEGFR and by cytoskeletal modulation via ERM and Rho kinase signaling. To assess the direct impact of RG7356 binding to the CD44 receptor, a global mass spectrometry-based phosphoproteomics approach was applied to freshly isolated MDA-MB-231 tumor xenografts. Results from a global phosphoproteomics screen were further corroborated by Western blot and ELISA analyses of tumor lysates from CD44-expressing tumors. Short-term treatment of tumor-bearing mice with RG7356 resulted in modifications of the MAPK pathway in the responsive model, although no effects on downstream phosphorylation were observed in a nonresponsive xenograft model. Taken together, our approach augments the value of other high throughput techniques to identify biomarkers for clinical development of targeted agents.

PMID:
22777824
DOI:
10.1158/0008-5472.CAN-12-0136
[Indexed for MEDLINE]
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