title: Early changes in protein expression detected by mass spectrometry predict tumor response to molecular therapeutics.
abstract: Biomarkers that predict therapeutic response are essential for the development of anticancer therapies. We have used matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) to directly analyze protein profiles in mouse mammary tumor virus/HER2 transgenic mouse frozen tumor sections after treatment with the erbB receptor inhibitors OSI-774 and Herceptin. Inhibition of tumor cell proliferation and induction of apoptosis and tumor reduction were predicted by a >80% reduction in thymosin beta4 and ubiquitin levels that were detectable after 16 hours of a single drug dose before any evidence of in situ cellular activity. These effects were time- and dose-dependent, and their spatial distribution in the tumor correlated with that of the small-molecule inhibitor OSI-774. In addition, they predicted for therapeutic synergy of OSI-774 and Herceptin as well as for drug resistance. These results suggest that drug-induced early proteomic changes as measured by MALDI-MS can be used to predict the therapeutic response to established and novel therapies.
authors.affiliation: Mass Spectrometry Research Center, Department of Biochemistry, Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Reyzer
authors.forename: Robert L
authors.initials: RL
authors.lastname: Caldwell
authors.forename: Teresa C
authors.initials: TC
authors.lastname: Dugger
authors.forename: James T
authors.initials: JT
authors.lastname: Forbes
authors.forename: Christoph A
authors.initials: CA
authors.lastname: Ritter
authors.forename: Marta
authors.initials: M
authors.lastname: Guix
authors.forename: Carlos L
authors.initials: CL
authors.lastname: Arteaga
authors.forename: Richard M
authors.initials: RM
authors.lastname: Caprioli
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor / Q000378:metabolism*; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D011237:Predictive Value of Tests; D047428:Protein Kinase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D020543:Proteome / Q000378:metabolism*; D011799:Quinazolines / Q000493:pharmacokinetics / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D000068878:Trastuzumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D047428:Protein Kinase Inhibitors; D020543:Proteome; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab