TY - JOUR
T1 - Homeobox B9 mediates resistance to anti-VEGF therapy in colorectal cancer patients
AU - Carbone, Carmine
AU - Piro, Geny
AU - Simionato, Francesca
AU - Ligorio, Francesca
AU - Cremolini, Chiara
AU - Loupakis, Fotios
AU - Alè, Greta
AU - Rossini, Daniele
AU - Merz, Valeria
AU - Santoro, Raffaela
AU - Zecchetto, Camilla
AU - Zanotto, Marco
AU - Di Nicolantonio, Federica
AU - Bardelli, Alberto
AU - Fontanini, Gabriella
AU - Tortora, Giampaolo
AU - Melisi, Davide
PY - 2017/8/1
Y1 - 2017/8/1
N2 - Purpose: The identification of predictive biomarkers for antiangiogenic therapies remains an unmeet need. We hypothesized that the transcription factor Homeobox B9 (HOXB9) could be responsible for the tumor resistance to the anti-VEGF agent bevacizumab. Experimental Design: HOXB9 expression and activation were measured in eight models of colorectal and pancreatic cancer with different resistance to bevacizumab. Serum levels of Angiopoie-tin-like Protein (Angptl)2, CXC receptor ligand (CXCL)1, IL8, and TGFb1 in tumor-bearing mice were measured by multiplex xMAP technology. HOXB9 expression was measured by immunohistochemical analysis in 81 pretreatment specimens from metastatic colorectal cancer patients. Differences in progression-free survival (PFS) were determined using a log-rank test. Results: HOXB9-positive tumors were resistant to bevacizumab, whereas mice bearing HOXB9-negative tumors were cured by this agent. Silencing HOXB9 in bevacizumab-resistant models significantly (P < 0.05) reduced Angptl2, CXCL1, IL8, and TGFb1 levels, reverted their mesenchymal phenotype, reduced CD11bþ cells infiltration, and restored, in turn, sensitivity to bevacizumab. HOXB9 had no prognostic value in patients treated with a first-line chemotherapeutic regimen noncontaining bevacizumab. However, patients affected by an HOXB9-negative tumor had a significantly longer PFS compared with those with an HOXB9-positive tumor if treated with a first-line regimen containing bevacizumab (18.0 months vs. 10.4 months; HR 2.037; 95% confidence interval, 1.006–4.125; P ¼ 0.048). Conclusions: These findings integrate the complexity of numerous mechanisms of anti-VEGF resistance into the single transcription factor HOXB9. Silencing HOXB9 could be a promising approach to modulate this resistance. Our results candidate HOXB9 as predictive biomarker for selecting colorectal cancer patients for antiangiogenic therapy.
AB - Purpose: The identification of predictive biomarkers for antiangiogenic therapies remains an unmeet need. We hypothesized that the transcription factor Homeobox B9 (HOXB9) could be responsible for the tumor resistance to the anti-VEGF agent bevacizumab. Experimental Design: HOXB9 expression and activation were measured in eight models of colorectal and pancreatic cancer with different resistance to bevacizumab. Serum levels of Angiopoie-tin-like Protein (Angptl)2, CXC receptor ligand (CXCL)1, IL8, and TGFb1 in tumor-bearing mice were measured by multiplex xMAP technology. HOXB9 expression was measured by immunohistochemical analysis in 81 pretreatment specimens from metastatic colorectal cancer patients. Differences in progression-free survival (PFS) were determined using a log-rank test. Results: HOXB9-positive tumors were resistant to bevacizumab, whereas mice bearing HOXB9-negative tumors were cured by this agent. Silencing HOXB9 in bevacizumab-resistant models significantly (P < 0.05) reduced Angptl2, CXCL1, IL8, and TGFb1 levels, reverted their mesenchymal phenotype, reduced CD11bþ cells infiltration, and restored, in turn, sensitivity to bevacizumab. HOXB9 had no prognostic value in patients treated with a first-line chemotherapeutic regimen noncontaining bevacizumab. However, patients affected by an HOXB9-negative tumor had a significantly longer PFS compared with those with an HOXB9-positive tumor if treated with a first-line regimen containing bevacizumab (18.0 months vs. 10.4 months; HR 2.037; 95% confidence interval, 1.006–4.125; P ¼ 0.048). Conclusions: These findings integrate the complexity of numerous mechanisms of anti-VEGF resistance into the single transcription factor HOXB9. Silencing HOXB9 could be a promising approach to modulate this resistance. Our results candidate HOXB9 as predictive biomarker for selecting colorectal cancer patients for antiangiogenic therapy.
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U2 - 10.1158/1078-0432.CCR-16-3153
DO - 10.1158/1078-0432.CCR-16-3153
M3 - Article
AN - SCOPUS:85027199952
VL - 23
SP - 4312
EP - 4322
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 15
ER -