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

Guido Giordano, Antonio Febbraro, Eugenio Tomaselli, Maria Lucia Sarnicola, Pietro Parcesepe, Domenico Parente, Nicola Forte, Alessio Fabozzi, Andrea Remo, Andrea Bonetti, Erminia Manfrin, Somayehsadat Ghasemi, Michele Ceccarelli, Luigi Cerulo, Flavia Bazzoni, Massimo Pancione

Research output: Contribution to journalArticle

27 Citations (Scopus)

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. Conclusion: 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.

Original languageEnglish
Article number108
JournalJournal of Experimental and Clinical Cancer Research
Volume34
Issue number1
DOIs
Publication statusPublished - 1 Oct 2015
Externally publishedYes

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MAP Kinase Kinase Kinases
Vascular Endothelial Growth Factor A
Colorectal Neoplasms
Neoplasms
Mitogen-Activated Protein Kinase Kinases
Colonic Neoplasms
CD3 Antigens
CD8 Antigens
Tumor Microenvironment
Computational Biology
Chemokines
Disease-Free Survival
Intercellular Signaling Peptides and Proteins
Phosphotransferases
Immunohistochemistry
Genome
Inflammation
T-Lymphocytes
Antigens
Drug Therapy

Keywords

  • CD15/FUT4
  • EGFR or VEGF
  • ERBB3 or FGFR4
  • Metastatic CRC

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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. / Giordano, Guido; Febbraro, Antonio; Tomaselli, Eugenio; Sarnicola, Maria Lucia; Parcesepe, Pietro; Parente, Domenico; Forte, Nicola; Fabozzi, Alessio; Remo, Andrea; Bonetti, Andrea; Manfrin, Erminia; Ghasemi, Somayehsadat; Ceccarelli, Michele; Cerulo, Luigi; Bazzoni, Flavia; Pancione, Massimo.

In: Journal of Experimental and Clinical Cancer Research, Vol. 34, No. 1, 108, 01.10.2015.

Research output: Contribution to journalArticle

Giordano, G, Febbraro, A, Tomaselli, E, Sarnicola, ML, Parcesepe, P, Parente, D, Forte, N, Fabozzi, A, Remo, A, Bonetti, A, Manfrin, E, Ghasemi, S, Ceccarelli, M, Cerulo, L, Bazzoni, F & Pancione, M 2015, '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', Journal of Experimental and Clinical Cancer Research, vol. 34, no. 1, 108. https://doi.org/10.1186/s13046-015-0225-7
Giordano, Guido ; Febbraro, Antonio ; Tomaselli, Eugenio ; Sarnicola, Maria Lucia ; Parcesepe, Pietro ; Parente, Domenico ; Forte, Nicola ; Fabozzi, Alessio ; Remo, Andrea ; Bonetti, Andrea ; Manfrin, Erminia ; Ghasemi, Somayehsadat ; Ceccarelli, Michele ; Cerulo, Luigi ; Bazzoni, Flavia ; Pancione, Massimo. / 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. In: Journal of Experimental and Clinical Cancer Research. 2015 ; Vol. 34, No. 1.
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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. Conclusion: 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.",
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T1 - 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

AU - Giordano, Guido

AU - Febbraro, Antonio

AU - Tomaselli, Eugenio

AU - Sarnicola, Maria Lucia

AU - Parcesepe, Pietro

AU - Parente, Domenico

AU - Forte, Nicola

AU - Fabozzi, Alessio

AU - Remo, Andrea

AU - Bonetti, Andrea

AU - Manfrin, Erminia

AU - Ghasemi, Somayehsadat

AU - Ceccarelli, Michele

AU - Cerulo, Luigi

AU - Bazzoni, Flavia

AU - Pancione, Massimo

PY - 2015/10/1

Y1 - 2015/10/1

N2 - 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. Conclusion: 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.

AB - 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. Conclusion: 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.

KW - CD15/FUT4

KW - EGFR or VEGF

KW - ERBB3 or FGFR4

KW - Metastatic CRC

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