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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.

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 - J. Exp. Clin. Cancer Res. (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Medical Oncology Unit, Fatebenefratelli Hospital, 82100, Benevento, Italy.

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.

No MeSH data available.


Related in: MedlinePlus

CD15/FUT4 expression pattern, inflammatory response and patients’ outcome in a larger cohort study. a Significant inverse correlation of NLR at diagnosis with tumor-associated CD3+ T-cells and CD8+ T- cytotoxic quantification (n = 99; expressed as mean of replicates cells counts, cells mm−2). b Correlation between NLR at diagnosis and tumor-related expression pattern of CD15/FUT4 spared into three subgroups negative, low and high, respectively. One dot represents NLR at diagnosis for each patient, P value was obtained by Mann–Whitney test. c Kaplan–Meier curves for progression-free survival and overall survival in the validation set (n = 102). The medians PFS value were 13, 10 and 5.5 months (HR = 3.37; 95 % CI = 2.14–5.51). The medians OS value were 38, 26 and 13 months for negative (n = 18), low (n = 40) and high-CD15/FUT4 (n = 44) expressing tumors, respectively (HR = 1.95; 95 % CI = 1.37–2.98). d Kaplan–Meier curves for progression-free survival and overall survival in relationship with NLR at diagnosis (cutoff value of 5). The medians PFS value were 12 and 6.5 months respectively (HR = 2.41; 95 % CI = 1.37–4.32). The medians OS value were 35 and 17 months with an NLR ≤5 (n = 30) and an NLR >5 (n = 72) patients respectively(HR = 2.39; 95 % CI = 1.48–3.85)
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Fig2: CD15/FUT4 expression pattern, inflammatory response and patients’ outcome in a larger cohort study. a Significant inverse correlation of NLR at diagnosis with tumor-associated CD3+ T-cells and CD8+ T- cytotoxic quantification (n = 99; expressed as mean of replicates cells counts, cells mm−2). b Correlation between NLR at diagnosis and tumor-related expression pattern of CD15/FUT4 spared into three subgroups negative, low and high, respectively. One dot represents NLR at diagnosis for each patient, P value was obtained by Mann–Whitney test. c Kaplan–Meier curves for progression-free survival and overall survival in the validation set (n = 102). The medians PFS value were 13, 10 and 5.5 months (HR = 3.37; 95 % CI = 2.14–5.51). The medians OS value were 38, 26 and 13 months for negative (n = 18), low (n = 40) and high-CD15/FUT4 (n = 44) expressing tumors, respectively (HR = 1.95; 95 % CI = 1.37–2.98). d Kaplan–Meier curves for progression-free survival and overall survival in relationship with NLR at diagnosis (cutoff value of 5). The medians PFS value were 12 and 6.5 months respectively (HR = 2.41; 95 % CI = 1.37–4.32). The medians OS value were 35 and 17 months with an NLR ≤5 (n = 30) and an NLR >5 (n = 72) patients respectively(HR = 2.39; 95 % CI = 1.48–3.85)

Mentions: Linear correlation analysis showed that high systemic inflammation is associated with lower immune-cells density, especially CD3+T cells (r =0.15; P < 0.01). A finding further supported by decreased infiltration of CD8+ for cytotoxic T cells (r = 0.26; P < 0.001; Fig. 2a and Additional file 3: Figure S2C, D).Fig 2


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 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 - J. Exp. Clin. Cancer Res. (2015)

CD15/FUT4 expression pattern, inflammatory response and patients’ outcome in a larger cohort study. a Significant inverse correlation of NLR at diagnosis with tumor-associated CD3+ T-cells and CD8+ T- cytotoxic quantification (n = 99; expressed as mean of replicates cells counts, cells mm−2). b Correlation between NLR at diagnosis and tumor-related expression pattern of CD15/FUT4 spared into three subgroups negative, low and high, respectively. One dot represents NLR at diagnosis for each patient, P value was obtained by Mann–Whitney test. c Kaplan–Meier curves for progression-free survival and overall survival in the validation set (n = 102). The medians PFS value were 13, 10 and 5.5 months (HR = 3.37; 95 % CI = 2.14–5.51). The medians OS value were 38, 26 and 13 months for negative (n = 18), low (n = 40) and high-CD15/FUT4 (n = 44) expressing tumors, respectively (HR = 1.95; 95 % CI = 1.37–2.98). d Kaplan–Meier curves for progression-free survival and overall survival in relationship with NLR at diagnosis (cutoff value of 5). The medians PFS value were 12 and 6.5 months respectively (HR = 2.41; 95 % CI = 1.37–4.32). The medians OS value were 35 and 17 months with an NLR ≤5 (n = 30) and an NLR >5 (n = 72) patients respectively(HR = 2.39; 95 % CI = 1.48–3.85)
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4590269&req=5

Fig2: CD15/FUT4 expression pattern, inflammatory response and patients’ outcome in a larger cohort study. a Significant inverse correlation of NLR at diagnosis with tumor-associated CD3+ T-cells and CD8+ T- cytotoxic quantification (n = 99; expressed as mean of replicates cells counts, cells mm−2). b Correlation between NLR at diagnosis and tumor-related expression pattern of CD15/FUT4 spared into three subgroups negative, low and high, respectively. One dot represents NLR at diagnosis for each patient, P value was obtained by Mann–Whitney test. c Kaplan–Meier curves for progression-free survival and overall survival in the validation set (n = 102). The medians PFS value were 13, 10 and 5.5 months (HR = 3.37; 95 % CI = 2.14–5.51). The medians OS value were 38, 26 and 13 months for negative (n = 18), low (n = 40) and high-CD15/FUT4 (n = 44) expressing tumors, respectively (HR = 1.95; 95 % CI = 1.37–2.98). d Kaplan–Meier curves for progression-free survival and overall survival in relationship with NLR at diagnosis (cutoff value of 5). The medians PFS value were 12 and 6.5 months respectively (HR = 2.41; 95 % CI = 1.37–4.32). The medians OS value were 35 and 17 months with an NLR ≤5 (n = 30) and an NLR >5 (n = 72) patients respectively(HR = 2.39; 95 % CI = 1.48–3.85)
Mentions: Linear correlation analysis showed that high systemic inflammation is associated with lower immune-cells density, especially CD3+T cells (r =0.15; P < 0.01). A finding further supported by decreased infiltration of CD8+ for cytotoxic T cells (r = 0.26; P < 0.001; Fig. 2a and Additional file 3: Figure S2C, D).Fig 2

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Medical Oncology Unit, Fatebenefratelli Hospital, 82100, Benevento, Italy.

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.

No MeSH data available.


Related in: MedlinePlus