title: Proteomics-based identification of biomarkers for predicting sensitivity to a PI3-kinase inhibitor in cancer.
abstract: To identify biomarkers for predicting sensitivity to phosphatidylinositol 3-kinase (PI3K) inhibitors, we have developed a proteomics-based approach. Using surface-enhanced laser desorption-ionization time-of-flight mass spectrometry (SELDI-TOF MS), we measured the expression of 393 proteins in 39 human cancer cell lines (JFCR-39), and combined it with our previously established chemosensitivity database to select for proteins whose expressions show significant correlations to drug sensitivities. This integrated approach allowed us to identify peaks from two proteins, 11.6 and 11.8 kDa, that showed significant correlations with the sensitivity to a PI3K inhibitor, LY294002. We found that the 11.8 kDa protein was a phosphorylated form of the 11.6 kDa protein. While the 11.8 kDa protein showed a positive correlation with the sensitivity to LY294002, the 11.6 kDa protein showed a negative correlation with that of the LY294002. The 11.6 kDa protein was purified chromatographically, and was identified by SELDI-TOF MS as the ribosomal P2 protein, which possesses two prospective phosphorylation sites. These results suggested that the phosphorylation status of the ribosomal P2 was responsible for determining the sensitivity to LY294002, and that the ribosomal P2 could be a potential biomarker for predicting chemosensitivity.
authors.affiliation: Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-10-6 Ariake, Tokyo 135-8550, Japan.
authors.forename: Tetsuyuki
authors.initials: T
authors.lastname: Akashi
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Nishimura
authors.forename: Rumi
authors.initials: R
authors.lastname: Wakatabe
authors.forename: Mieko
authors.initials: M
authors.lastname: Shiwa
authors.forename: Takao
authors.initials: T
authors.lastname: Yamori
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage; D014408:Biomarkers, Tumor / Q000032:analysis*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002867:Chromones / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009025:Morpholines / Q000008:administration & dosage*; D009363:Neoplasm Proteins / Q000032:analysis*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020543:Proteome / Q000378:metabolism*; D040901:Proteomics / Q000379:methods; D012680:Sensitivity and Specificity; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D002867:Chromones; D009025:Morpholines; D009363:Neoplasm Proteins; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020543:Proteome; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one