title: Cancer-related CD15/FUT4 overexpression decreases benefit to agents targeting EGFR or VEGF acting as a novel RAF-MEK-ERK kinase downstream regulator in metastatic colorectal cancer.
abstract: BACKGROUND
  Cancer-related immune antigens in the tumor microenvironment could represent an obstacle to agents targeting EGFR "cetuximab" or VEGF "bevacizumab" in metastatic colorectal cancer (mCRC) patients.
  
  
  METHODS
  Infiltrating immune cells into tumor tissues, cancer-related expression of immune antigens (CD3, CD8, CD68, CD73, MPO, CD15/FUT4) from 102 mCRC patients receiving first-line Cetuximab or Bevacizumab plus chemotherapy were assessed by immunohistochemistry and validated in an independent tissue microarrays of 140 patients. Genome-wide expression profiles from 436 patients and 60 colon cancer cell lines were investigated using bioinformatics analysis. In vitro kinase assays of target genes activated by chemokines or growth factors were performed.
  
  
  RESULTS
  Here, we report that cancer-related CD15/FUT4 is overexpressed in most of mCRCs patients (43 %) and associates with lower intratumoral CD3+ and CD8+ T cells, higher systemic inflammation (NLR at diagnosis >5) and poorer outcomes, in terms of response and progression-free survival than those CD15/FUT4-low or negative ones (adjusted hazard ratio (HR) = 2.92; 95 % CI = 1.86-4.41; P < 0.001). Overexpression of CD15/FUT4 is induced through RAF-MEK-ERK kinase cascade, suppressed by MEK inhibitors and exhibits a close connection with constitutive oncogenic signalling pathways that respond to ERBB3 or FGFR4 activation (P < 0.001). CD15/FUT4-high expressing colon cancer cells with primary resistance to cetuximab or bevacizumab are significantly more sensitive to MEK inhibitors than CD15/FUT4-low counterparts.
  
  
  CONCLUSIONS
  Cancer-related CD15/FUT4 overexpression participates in cetuximab or bevacizumab mechanisms of resistance in mCRC patients. CD15/FUT4 as a potential target of the antitumor immune response requires further evaluation in clinical studies.
authors.affiliation: Medical Oncology Unit, Fatebenefratelli Hospital, 82100, Benevento, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Giordano
authors.affiliation: Medical Oncology Unit, Fatebenefratelli Hospital, 82100, Benevento, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Febbraro
authors.affiliation: Department of Clinical Pathology, Fatebenefratelli Hospital, 82100, Benevento, Italy.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Tomaselli
authors.affiliation: National Institute of Molecular Genetics "Romeo and Enrica Invernizzi", Milan, Italy.
authors.forename: Maria Lucia
authors.initials: ML
authors.lastname: Sarnicola
authors.affiliation: Department of Pathology and Diagnostics, University of Verona, 31134, Verona, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Parcesepe
authors.affiliation: Department of Clinical Pathology, Fatebenefratelli Hospital, 82100, Benevento, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Parente
authors.affiliation: Department of Clinical Pathology, Fatebenefratelli Hospital, 82100, Benevento, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Forte
authors.affiliation: Medical Oncology Unit, Fatebenefratelli Hospital, 82100, Benevento, Italy.
authors.forename: Alessio
authors.initials: A
authors.lastname: Fabozzi
authors.affiliation: Department of Pathology and Oncology, "Mater Salutis" Hospital, 37045, Legnago, Verona, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Remo
authors.affiliation: Department of Pathology and Oncology, "Mater Salutis" Hospital, 37045, Legnago, Verona, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Bonetti
authors.affiliation: Department of Pathology and Diagnostics, University of Verona, 31134, Verona, Italy.
authors.forename: Erminia
authors.initials: E
authors.lastname: Manfrin
authors.affiliation: Department of Pathology and Diagnostics, University of Verona, 31134, Verona, Italy.
authors.forename: Somayehsadat
authors.initials: S
authors.lastname: Ghasemi
authors.affiliation: Bioinformatics Laboratory, BIOGEM scrl, Ariano Irpino, Avellino, Italy.|Department of Sciences and Technologies, University of Sannio, Via Port'Arsa, 1182100, Benevento, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Ceccarelli
authors.affiliation: Bioinformatics Laboratory, BIOGEM scrl, Ariano Irpino, Avellino, Italy.|Department of Sciences and Technologies, University of Sannio, Via Port'Arsa, 1182100, Benevento, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Cerulo
authors.affiliation: Department of Pathology and Diagnostics, University of Verona, 31134, Verona, Italy.
authors.forename: Flavia
authors.initials: F
authors.lastname: Bazzoni
authors.affiliation: Department of Sciences and Technologies, University of Sannio, Via Port'Arsa, 1182100, Benevento, Italy. massimo.pancione@unisannio.it.
authors.forename: Massimo
authors.initials: M
authors.lastname: Pancione
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D000068258:Bevacizumab / Q000627:therapeutic use; D014408:Biomarkers, Tumor; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D000068818:Cetuximab / Q000627:therapeutic use; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology*; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005647:Fucosyltransferases / Q000096:biosynthesis*; D006801:Humans; D007249:Inflammation / Q000276:immunology; D016256:Lewis X Antigen / Q000096:biosynthesis*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D012189:Retrospective Studies; D059016:Tumor Microenvironment / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D048490:raf Kinases / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D016256:Lewis X Antigen; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; C066693:FUT4 protein, human; D005647:Fucosyltransferases; C512478:EGFR protein, human; D066246:ErbB Receptors; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D000068818:Cetuximab