Increased PDGFR-beta and VEGFR-2 protein levels are associated with resistance to platinum-based chemotherapy and adverse outcome of ovarian cancer patients

// Stefanie Avril 1, 4, * , Yasemin Dincer 1, * , Katharina Malinowsky 1 , Claudia Wolff 1 , Sibylle Gundisch 1 , Alexander Hapfelmeier 2 , Melanie Boxberg 1 , Holger Bronger 3 , Karl-Friedrich Becker 1 and Barbara Schmalfeldt 3, 5 1 Institute of Pathology, Technische Universitat Munchen, Munich, Germany 2 Institute of Medical Statistics and Epidemiology, Technische Universitat Munchen, Munich, Germany 3 Department of Obstetrics and Gynecology, Technische Universitat Munchen, Munich, Germany 4 Current address: Department of Pathology, Case Western Reserve University School of Medicine, University Hospitals Cleveland Medical Center and Case Comprehensive Cancer Center, Cleveland, Ohio, United States 5 Current address: Department of Gynecology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany * These authors contributed equally to this work Correspondence to: Karl-Friedrich Becker, email: kf.becker@tum.de Keywords: phosphoproteomics, reverse phase protein array (RPPA), ovarian cancer, platinum chemotherapy resistance, response prediction Received: January 27, 2017      Accepted: May 05, 2017      Published: June 08, 2017 ABSTRACT Despite frequent initial response rates of epithelial ovarian cancer to platinum-based chemotherapy the majority of patients develop drug resistance. Our aim was to evaluate differential expression of signaling-pathway proteins in platinum-sensitive versus platinum-resistant primary epithelial ovarian cancer specimens to identify predictive biomarkers for treatment response. 192 patients were studied comprising of independent training ( n = 89) and validation ( n = 103) cohorts. Full-length proteins were extracted from paraffin-embedded samples including multiple regions per tumor to account for intratumoral heterogeneity. Quantitative reverse-phase-protein-arrays were used to analyze protein and phospho-protein levels of 41 signaling molecules including growth-factor receptors, AKT and MAPK signaling pathways as well as angiogenesis and cell-adhesion. Platinum-resistant ovarian cancers (56/192) demonstrated significantly higher intratumoral levels of the angiogenesis-associated growth-factor receptors PDGFR-beta and VEGFR2 compared to platinum-sensitive tumors. In addition, patients with high PDGFR-beta expression had significantly shorter overall and progression-free survival (HR 3.6 and 2.4; p < 0.001). The prognostic value of PDGFR-beta and VEGFR2 was confirmed in publicly available microarray-datasets. High intratumoral levels of the angiogenesis-related growth-factor receptors PDGFR-beta and VEGFR2 might serve as novel predictive biomarkers to identify primary resistance to platinum-based chemotherapy. Those ovarian cancer patients might particularly benefit from additional anti-vascular therapy including anti-VEGF antibody or receptor tyrosine-kinase-inhibitor therapy.