title: Quantitative proteomic profiling identifies protein correlates to EGFR kinase inhibition.
abstract: Clinical oncology is hampered by lack of tools to accurately assess a patient's response to pathway-targeted therapies. Serum and tumor cell surface proteins whose abundance, or change in abundance in response to therapy, differentiates patients responding to a therapy from patients not responding to a therapy could be usefully incorporated into tools for monitoring response. Here, we posit and then verify that proteomic discovery in in vitro tissue culture models can identify proteins with concordant in vivo behavior and further, can be a valuable approach for identifying tumor-derived serum proteins. In this study, we use stable isotope labeling of amino acids in culture (SILAC) with proteomic technologies to quantitatively analyze the gefitinib-related protein changes in a model system for sensitivity to EGF receptor (EGFR)-targeted tyrosine kinase inhibitors. We identified 3,707 intracellular proteins, 1,276 cell surface proteins, and 879 shed proteins. More than 75% of the proteins identified had quantitative information, and a subset consisting of 400 proteins showed a statistically significant change in abundance following gefitinib treatment. We validated the change in expression profile in vitro and screened our panel of response markers in an in vivo isogenic resistant model and showed that these were markers of gefitinib response and not simply markers of phospho-EGFR downregulation. In doing so, we also were able to identify which proteins might be useful as markers for monitoring response and which proteins might be useful as markers for a priori prediction of response.
authors.affiliation: University of Southern California, Los Angeles, CA 90033, USA.
authors.forename: Kian
authors.initials: K
authors.lastname: Kani
authors.forename: Vitor M
authors.initials: VM
authors.lastname: Faca
authors.forename: Lindsey D
authors.initials: LD
authors.lastname: Hughes
authors.forename: Wenxuan
authors.initials: W
authors.lastname: Zhang
authors.forename: Qiaojun
authors.initials: Q
authors.lastname: Fang
authors.forename: Babak
authors.initials: B
authors.lastname: Shahbaba
authors.forename: Roland
authors.initials: R
authors.lastname: Luethy
authors.forename: Jonathan
authors.initials: J
authors.lastname: Erde
authors.forename: Joanna
authors.initials: J
authors.lastname: Schmidt
authors.forename: Sharon J
authors.initials: SJ
authors.lastname: Pitteri
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Katz
authors.forename: Mitchell E
authors.initials: ME
authors.lastname: Gross
authors.forename: Sylvia K
authors.initials: SK
authors.lastname: Plevritis
authors.forename: Martin W
authors.initials: MW
authors.lastname: McIntosh
authors.forename: Anjali
authors.initials: A
authors.lastname: Jain
authors.forename: Samir
authors.initials: S
authors.lastname: Hanash
authors.forename: David B
authors.initials: DB
authors.lastname: Agus
authors.forename: Parag
authors.initials: P
authors.lastname: Mallick
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D020543:Proteome; D040901:Proteomics; D011799:Quinazolines / Q000494:pharmacology; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D020543:Proteome; D011799:Quinazolines; D066246:ErbB Receptors; D000077156:Gefitinib