title: Involvement of signaling molecules in the prediction of response to imatinib treatment in metastatic GIST patients.
abstract: Imatinib therapy has undoubtedly contributed to the treatment of metastatic gastrointestinal stromal (GIST) tumors that were previously untreatable. However, disease progression during treatment with tyrosine kinase inhibitors remains an issue in clinical practice not fully explained by KIT and PDGFRA mutation status. We investigated the role of three important signaling molecules (insulin-like growth factor 1 receptor [IGF1R], protein kinase C-θ [PKCθ], and Raf kinase inhibitor protein [RKIP]) that have been implicated in GIST pathogenesis as potential biomarkers for prediction of response to imatinib treatment. We retrospectively reviewed 76 patients with metastatic GIST submitted to imatinib treatment between 2002 and 2007, and analyzed 63 of them. Insulin-like growth factor 1, total PKCθ, phosphorylated PKCθ, and RKIP immunohistochemical expression were correlated with objective response to imatinib treatment and progression-free and overall survival. Median follow-up was 31.2 mo (95% confidence interval, 26.3-36.1 mo). There was a statistically significant association between IGF1R expression and type of response to imatinib treatment (P = 0.05)-that is, higher IGF1R expression was related to lower objective response. However, IGF1R higher expression did not affect progression-free and overall survival. Insulin-like growth factor 1, but not PKCθ and RKIP, emerges as a potential biomarker for prediction of response to imatinib treatment in metastatic GISTs. Validation studies are warranted.
authors.affiliation: Coordination of Clinical Research, Instituto Nacional de Câncer, Rio de Janeiro, Brazil.
authors.forename: Marcus
authors.initials: M
authors.lastname: Valadão
authors.forename: Danielle
authors.initials: D
authors.lastname: Braggio
authors.forename: Anna Flávia
authors.initials: AF
authors.lastname: Santos
authors.forename: Haynna Kimie
authors.initials: HK
authors.lastname: Pimenta-Inada
authors.forename: Eduardo
authors.initials: E
authors.lastname: Linhares
authors.forename: Rinaldo
authors.initials: R
authors.lastname: Gonçalves
authors.forename: Sérgio
authors.initials: S
authors.lastname: Romano
authors.forename: Bruno
authors.initials: B
authors.lastname: Vilhena
authors.forename: Isabele
authors.initials: I
authors.lastname: Small
authors.forename: Daniel
authors.initials: D
authors.lastname: Cubero
authors.forename: Felipe
authors.initials: F
authors.lastname: Cruz
authors.forename: Antônio Talvane
authors.initials: AT
authors.lastname: Oliveira
authors.forename: Olga
authors.initials: O
authors.lastname: Martinho
authors.forename: Rui Manuel
authors.initials: RM
authors.lastname: Reis
authors.forename: Denise Peixoto
authors.initials: DP
authors.lastname: Guimarães
authors.forename: Carlos Gil
authors.initials: CG
authors.lastname: Ferreira
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides; D005260:Female; D005500:Follow-Up Studies; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D049488:Phosphatidylethanolamine Binding Protein / Q000378:metabolism; D010879:Piperazines / Q000627:therapeutic use*; D011237:Predictive Value of Tests; D011493:Protein Kinase C / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D011743:Pyrimidines / Q000627:therapeutic use*; D020239:Receptor Cross-Talk / Q000187:drug effects / Q000502:physiology; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics; D012189:Retrospective Studies; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; C511482:PEBP1 protein, human; D049488:Phosphatidylethanolamine Binding Protein; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D017526:Receptor, IGF Type 1; D020796:Receptor, Platelet-Derived Growth Factor alpha; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D011493:Protein Kinase C