title: Comparison of global versus epidermal growth factor receptor pathway profiling for prediction of lapatinib sensitivity in bladder cancer.
abstract: Chemotherapy for metastatic bladder cancer is rarely curative. The recently developed small molecule, lapatinib, a dual epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor-2 receptor tyrosine kinase inhibitor, might improve this situation. Recent findings suggest that identifying which patients are likely to benefit from targeted therapies is beneficial, although controversy remains regarding what types of evaluation might yield optimal candidate biomarkers of sensitivity. Here, we address this issue by developing and comparing lapatinib sensitivity prediction models for human bladder cancer cells. After empirically determining in vitro sensitivities (drug concentration necessary to cause a 50% growth inhibition) of a panel of 39 such lines to lapatinib treatment, we developed prediction models based on profiling the baseline transcriptome, the phosphorylation status of EGFR pathway signaling targets, or a combination of both data sets. We observed that models derived from microarray gene expression data showed better prediction performance (93%-98% accuracy) compared with models derived from EGFR pathway profiling of 23 selected phosphoproteins known to be involved in EGFR-driven signaling (54%-61% accuracy) or from a subset of the microarray data for transcripts in the EGFR pathway (86% accuracy). Combining microarray data and phosphoprotein profiling provided a combination model with 98% accuracy. Our findings suggest that transcriptome-wide profiling for biomarkers of lapatinib sensitivity in cancer cells provides models with excellent predictive performance and may be effectively combined with EGFR pathway phosphoprotein profiling data. These results have significant implications for the use of such tools in personalizing the approach to cancers treated with EGFR-directed targeted therapies.
authors.affiliation: Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908, USA.
authors.forename: Dmytro M
authors.initials: DM
authors.lastname: Havaleshko
authors.forename: Steven Christopher
authors.initials: SC
authors.lastname: Smith
authors.forename: HyungJun
authors.initials: H
authors.lastname: Cho
authors.forename: Sooyoung
authors.initials: S
authors.lastname: Cheon
authors.forename: Charles R
authors.initials: CR
authors.lastname: Owens
authors.forename: Jae K
authors.initials: JK
authors.lastname: Lee
authors.forename: Lance A
authors.initials: LA
authors.lastname: Liotta
authors.forename: Virginia
authors.initials: V
authors.lastname: Espina
authors.forename: Julia D
authors.initials: JD
authors.lastname: Wulfkuhle
authors.forename: Emanuel F
authors.initials: EF
authors.lastname: Petricoin
authors.forename: Dan
authors.initials: D
authors.lastname: Theodorescu
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression; D020869:Gene Expression Profiling / Q000379:methods*; D006801:Humans; D000077341:Lapatinib; D008958:Models, Molecular; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011799:Quinazolines / Q000627:therapeutic use*; D012680:Sensitivity and Specificity; D015398:Signal Transduction / Q000187:drug effects; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D011799:Quinazolines; D000077341:Lapatinib; D066246:ErbB Receptors