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A protein expression signature for drug response

Posted by Daniel Liebler on Friday, February 24, 2012 in News.

Graduate student Matt Myers’ dissertation project asked the question, “Can protein expression changes indicate responses to drug inhibition of a signaling network?”  Matt’s recent paper in Molecular and Cellular Proteomics studied epidermal growth factor receptor (EGFR) signaling, which is the target of several anticancer drugs.  He used shotgun proteomic analysis to compare the proteomes of EGF-stimulated A431 carcinoma cells with the proteomes of EGF-treated cells also treated with either the tyrosine kinase inhibitor gefitinib or the anti-EGFR antibody cetuximab.  The comparisons identified a dozen proteins whose EGF-dependent expression changes were reversed by both drugs.  Matt’s dissertation committee suggested that he focus on these dozen proteins as possible markers for EGFR inhibition in other systems.  Matt used an MRM assay panel to measure expression changes in these proteins in cell models that are responsive or resistant to EGFR inhibitors.  In the responsive cells, the markers changed levels as in the A431 model, whereas no changes were measured in the resistant cells.   In archival FFPE tissues from a cetuximab-responsive mouse colon tumor xenograft model, most of the detectable marker proteins exhibited the expected response to treatment.  In cetuximab-resistant xenografts, no changes in the markers were measured.  Finally, Matt was able to detect cetuximab-dependent changes in several of the markers detected in stomach tissue biopsies from a patient with Menetrier’s disease, a hyperproliferative disorder of the stomach lining.  Matt’s study establishes that protein expression changes can indicate response of a signaling network to targeted therapeutics.  The importance of this work is that protein expression changes are robust and easier to measure than changes in the phosphorylation states of network proteins, particularly in tissue biopsies or FFPE specimens.  We are further exploring this approach to the development of companion diagnostics for cancer therapeutics.  Matt successfully defended his dissertation and completed his Ph.D. just before Christmas.  We wish him the best in his new postdoc position.

 

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