title: EGFR kinase-dependent and kinase-independent roles in clear cell renal cell carcinoma.
abstract: Epidermal growth factor receptor (EGFR) is associated with progression of many epithelial malignancies and represents a significant therapeutic target. Although clear cell renal cell carcinoma (CCRCC) has been widely investigated for EGFR molecular alterations, genetic evidences of EGFR gene activating mutations and/or gene amplification have been rarely confirmed in the literature. Therefore, until now EGFR-targeted therapies in clinical trials have been demonstrated unsuccessful. New evidence has been given about the interactions between EGFR and the sodium glucose co-transporter-1 (SGLT1) in maintaining the glucose basal intracellular level to favour cancer cell growth and survival; thus a new functional role may be attributed to EGFR, regardless of its kinase activity. To define the role of EGFR in CCRCC an extensive investigation of genetic changes and functional kinase activities was performed in a series of tumors by analyzing the EGFR mutational status and expression profile, together with the protein expression of downstream signaling pathways members. Furthermore, we investigated the co-expression of EGFR and SGLT1 proteins and their relationships with clinic-pathological features in CCRCC. EGFR protein expression was identified in 98.4% of CCRCC. Furthermore, it was described for the first time that SGLT1 is overexpressed in CCRCC (80.9%), and that co-expression with EGFR is appreciable in 79.4% of the tumours. Moreover, the activation of downstream EGFR pathways was found in about 79.4% of SGLT1-positive CCRCCs. The mutational status analysis of EGFR failed to demonstrate mutations on exons 18 to 24 and the presence of EGFR-variantIII (EGFRvIII) in all CCRCCs analyzed. FISH analysis revealed absence of EGFR amplification, and high polysomy of chromosome 7. Finally, the EGFR gene expression profile showed gene overexpression in 38.2% of CCRCCs. Our study contributes to define the complexity of EGFR role in CCRCC, identifying its bivalent kinase-dependent and kinase-independent functions, both potentially involved in CCRCC progression. These results might have important implications on therapeutic approaches to CCRCC, since the disruption of the interaction between EGFR/SGLT1, mediated by anti-EGFR antibodies and/or SGLT1 inhibitors, might constitute a novel therapeutic target for CCRCC treatment, and new clinical trials should be evaluated on the basis of this therapeutic proposal.
authors.affiliation: Department of Clinical and Experimental Medicine, University of SassariSassari, Italy; Department of Diagnostic Services, Surgical Pathology Unit, "Giovanni Paolo II" Hospital, ASL OlbiaOlbia, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Cossu-Rocca
authors.affiliation: Department of Clinical and Experimental Medicine, University of Sassari Sassari, Italy.
authors.forename: Maria R
authors.initials: MR
authors.lastname: Muroni
authors.affiliation: Department of Clinical and Experimental Medicine, University of Sassari Sassari, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Sanges
authors.affiliation: Epidemiology and Medical Statistics Unit, Department of Biomedical Sciences, University of Sassari, Research, Medical Education and Professional Development Unit, AOU Sassari Sassari, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Sotgiu
authors.affiliation: Department of Pathology, Azienda Ospedaliera Brotzu Cagliari, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Asunis
authors.affiliation: Department of Oncology, "A. Businco" Oncologic Hospital, ASL Cagliari Cagliari, Italy.
authors.forename: Luciana
authors.initials: L
authors.lastname: Tanca
authors.affiliation: Department of Pathology, Azienda Ospedaliera Brotzu Cagliari, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Onnis
authors.affiliation: Department of Biomedical Sciences, University of Sassari Sassari, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Pira
authors.affiliation: Department of Pathology, AOU Sassari Sassari, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Manca
authors.affiliation: Epidemiology and Medical Statistics Unit, Department of Biomedical Sciences, University of Sassari, Research, Medical Education and Professional Development Unit, AOU Sassari Sassari, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Dore
authors.affiliation: Department of Pathology, AOU Sassari Sassari, Italy.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Uras
authors.affiliation: Department of Biomedical Sciences, University of Sassari Sassari, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Ena
authors.affiliation: Department of Clinical and Experimental Medicine, University of Sassari Sassari, Italy.
authors.forename: Maria R
authors.initials: MR
authors.lastname: De Miglio
keywords: Clear cell renal cell carcinoma; EGFR; EGFR-variantIII; FISH analysis; SGLT1; kinase-dependent EGFR function; kinase-independent EGFR function; p-STAT3; p-p44/42 MAPK; pAKT