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

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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.

Electronic supplementary material

The online version of this article (doi:10.1186/s13046-015-0225-7) contains supplementary material, which is available to authorized users.

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Most cited references 24

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Drug resistance and the solid tumor microenvironment.

Olivier Trédan, Carlos M. Galmarini, Krupa Patel … (2007)

Resistance of human tumors to anticancer drugs is most often ascribed to gene mutations, gene amplification, or epigenetic changes that influence the uptake, metabolism, or export of drugs from single cells. Another important yet little-appreciated cause of anticancer drug resistance is the limited ability of drugs to penetrate tumor tissue and to reach all of the tumor cells in a potentially lethal concentration. To reach all viable cells in the tumor, anticancer drugs must be delivered efficiently through the tumor vasculature, cross the vessel wall, and traverse the tumor tissue. In addition, heterogeneity within the tumor microenvironment leads to marked gradients in the rate of cell proliferation and to regions of hypoxia and acidity, all of which can influence the sensitivity of the tumor cells to drug treatment. In this review, we describe how the tumor microenvironment may be involved in the resistance of solid tumors to chemotherapy and discuss potential strategies to improve the effectiveness of drug treatment by modifying factors relating to the tumor microenvironment.

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Predicting immunogenic tumour mutations by combining mass spectrometry and exome sequencing.

Mahesh Yadav, Suchit Jhunjhunwala, Qui Phung … (2014)

Human tumours typically harbour a remarkable number of somatic mutations. If presented on major histocompatibility complex class I molecules (MHCI), peptides containing these mutations could potentially be immunogenic as they should be recognized as 'non-self' neo-antigens by the adaptive immune system. Recent work has confirmed that mutant peptides can serve as T-cell epitopes. However, few mutant epitopes have been described because their discovery required the laborious screening of patient tumour-infiltrating lymphocytes for their ability to recognize antigen libraries constructed following tumour exome sequencing. We sought to simplify the discovery of immunogenic mutant peptides by characterizing their general properties. We developed an approach that combines whole-exome and transcriptome sequencing analysis with mass spectrometry to identify neo-epitopes in two widely used murine tumour models. Of the >1,300 amino acid changes identified, ∼13% were predicted to bind MHCI, a small fraction of which were confirmed by mass spectrometry. The peptides were then structurally modelled bound to MHCI. Mutations that were solvent-exposed and therefore accessible to T-cell antigen receptors were predicted to be immunogenic. Vaccination of mice confirmed the approach, with each predicted immunogenic peptide yielding therapeutically active T-cell responses. The predictions also enabled the generation of peptide-MHCI dextramers that could be used to monitor the kinetics and distribution of the anti-tumour T-cell response before and after vaccination. These findings indicate that a suitable prediction algorithm may provide an approach for the pharmacodynamic monitoring of T-cell responses as well as for the development of personalized vaccines in cancer patients.

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Experimentally derived metastasis gene expression profile predicts recurrence and death in patients with colon cancer.

J Smith, Natasha Deane, Fei Wu … (2010)

Staging inadequately predicts metastatic risk in patients with colon cancer. We used a gene expression profile derived from invasive, murine colon cancer cells that were highly metastatic in an immunocompetent mouse model to identify patients with colon cancer at risk of recurrence. This phase 1, exploratory biomarker study used 55 patients with colorectal cancer from Vanderbilt Medical Center (VMC) as the training dataset and 177 patients from the Moffitt Cancer Center as the independent dataset. The metastasis-associated gene expression profile developed from the mouse model was refined with comparative functional genomics in the VMC gene expression profiles to identify a 34-gene classifier associated with high risk of metastasis and death from colon cancer. A metastasis score derived from the biologically based classifier was tested in the Moffitt dataset. A high score was significantly associated with increased risk of metastasis and death from colon cancer across all pathologic stages and specifically in stage II and stage III patients. The metastasis score was shown to independently predict risk of cancer recurrence and death in univariate and multivariate models. For example, among stage III patients, a high score translated to increased relative risk of cancer recurrence (hazard ratio, 4.7; 95% confidence interval, 1.566-14.05). Furthermore, the metastasis score identified patients with stage III disease whose 5-year recurrence-free survival was >88% and for whom adjuvant chemotherapy did not increase survival time. A gene expression profile identified from an experimental model of colon cancer metastasis predicted cancer recurrence and death, independently of conventional measures, in patients with colon cancer. Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

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Author and article information

Contributors

Massimo Pancione: 0039 0824 305157 , massimo.pancione@unisannio.it

Journal

Journal ID (nlm-ta): J Exp Clin Cancer Res

Journal ID (iso-abbrev): J. Exp. Clin. Cancer Res

Title: Journal of Experimental & Clinical Cancer Research : CR

Publisher: BioMed Central (London )

ISSN (Print): 0392-9078

ISSN (Electronic): 1756-9966

Publication date (Electronic): 1 October 2015

Publication date PMC-release: 1 October 2015

Publication date Collection: 2015

Volume: 34

Electronic Location Identifier: 108

Affiliations

[ ]Medical Oncology Unit, Fatebenefratelli Hospital, 82100 Benevento, Italy

[ ]Department of Clinical Pathology, Fatebenefratelli Hospital, 82100 Benevento, Italy

[ ]National Institute of Molecular Genetics “Romeo and Enrica Invernizzi”, Milan, Italy

[ ]Department of Pathology and Diagnostics, University of Verona, 31134 Verona, Italy

[ ]Department of Pathology and Oncology, “Mater Salutis” Hospital, 37045 Legnago, Verona Italy

[ ]Bioinformatics Laboratory, BIOGEM scrl, Ariano Irpino, Avellino, Italy

[ ]Department of Sciences and Technologies, University of Sannio, Via Port’Arsa, 1182100 Benevento, Italy

Article

Publisher ID: 225

DOI: 10.1186/s13046-015-0225-7

PMC ID: 4590269

PubMed ID: 26427914

SO-VID: 5c532902-b42e-4bb5-8edf-960cb8f278a6

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 10 July 2015

Date accepted : 24 September 2015

Custom metadata

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: cd15/fut4,egfr or vegf,erbb3 or fgfr4,metastatic crc

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: cd15/fut4, egfr or vegf, erbb3 or fgfr4, metastatic crc

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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

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Abstract

Background

Methods

Results

Conclusion

Electronic supplementary material

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Karger: Oncology

Most cited references 24

Drug resistance and the solid tumor microenvironment.

Predicting immunogenic tumour mutations by combining mass spectrometry and exome sequencing.

Experimentally derived metastasis gene expression profile predicts recurrence and death in patients with colon cancer.

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Article

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Cited by 36

Most referenced authors 1,259