EPHA2 Is a Predictive Biomarker of Resistance and a Potential Therapeutic Target for Improving Antiepidermal Growth Factor Receptor Therapy in Colorectal Cancer

Giulia Martini, Claudia Cardone, Pietro Paolo Vitiello, Valentina Belli, Stefania Napolitano, Teresa Troiani, Davide Ciardiello, Carminia Maria Della Corte, Floriana Morgillo, Nunzia Matrone, Vincenzo Sforza, Gianpaolo Papaccio, Vincenzo Desiderio, Mariel C Paul, Veronica Moreno-Viedma, Nicola Normanno, Anna Maria Rachiglio, Virginia Tirino, Evaristo Maiello, Tiziana Pia Latiano & 5 others Daniele Rizzi, Giuseppe Signoriello, Maria Sibilia, Fortunato Ciardiello, Erika Martinelli

Research output: Contribution to journalArticle

Abstract

The EPHA2 tyrosine kinase receptor is implicated in tumor progression and targeted therapies resistance. We evaluated EPHA2 as a potential resistance marker to the antiepidermal growth factor receptor (EGFR) monoclonal antibody cetuximab in colorectal cancer. We studied activation of EPHA2 in a panel of human colorectal cancer cell lines sensitive or resistant to anti-EGFR drugs. The in vitro and in vivo effects of ALW-II-41-27 (an EPHA2 inhibitor) and/or cetuximab treatment were tested. Formalin-fixed paraffin-embedded tumor specimens from 82 RAS wild-type (WT) metastatic colorectal cancer patients treated with FOLFIRI + cetuximab as first-line therapy in the CAPRI-GOIM trial were assessed for EPHA2 expression by immunohistochemistry and correlated with treatment efficacy. EPHA2 was differentially activated in colorectal cancer cell lines. Combined treatment with ALW-II-41-27 plus cetuximab reverted primary and acquired resistance to cetuximab, causing cell growth inhibition, inducing apoptosis and cell-cycle G1-G2 arrest. In tumor xenograft models, upon progression to cetuximab, ALW-II-41-27 addition significantly inhibited tumor growth. EPHA2 protein expression was detected in 55 of 82 tumor samples, frequently expressed in less-differentiated and left-sided tumors. High levels of EPHA2 significantly correlated with worse progression-free survival [8.6 months; confidence interval (CI) 95%, 6.4-10.8; vs. 12.3 months; CI 95%, 10.4-14.2; P = 0.03] and with increased progression rate (29% vs. 9%, P = 0.02). A specific EPHA2 inhibitor reverts in vitro and in vivo primary and acquired resistance to anti-EGFR therapy. EPHA2 levels are significantly associated with worse outcome in patients treated with FOLFIRI + cetuximab. These results highlight EPHA2 as a potential therapeutic target in metastatic colorectal cancer.

Original languageEnglish
Pages (from-to)845-855
Number of pages11
JournalMolecular Cancer Therapeutics
Volume18
Issue number4
DOIs
Publication statusPublished - Apr 2019

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Growth Factor Receptors
Colorectal Neoplasms
Biomarkers
Neoplasms
Therapeutics
G2 Phase Cell Cycle Checkpoints
Confidence Intervals
G1 Phase Cell Cycle Checkpoints
Cell Line
Receptor Protein-Tyrosine Kinases
Growth
Cetuximab
Heterografts
Paraffin
Formaldehyde
Disease-Free Survival
Immunohistochemistry
Monoclonal Antibodies
Apoptosis
Pharmaceutical Preparations

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EPHA2 Is a Predictive Biomarker of Resistance and a Potential Therapeutic Target for Improving Antiepidermal Growth Factor Receptor Therapy in Colorectal Cancer. / Martini, Giulia; Cardone, Claudia; Vitiello, Pietro Paolo; Belli, Valentina; Napolitano, Stefania; Troiani, Teresa; Ciardiello, Davide; Della Corte, Carminia Maria; Morgillo, Floriana; Matrone, Nunzia; Sforza, Vincenzo; Papaccio, Gianpaolo; Desiderio, Vincenzo; Paul, Mariel C; Moreno-Viedma, Veronica; Normanno, Nicola; Rachiglio, Anna Maria; Tirino, Virginia; Maiello, Evaristo; Latiano, Tiziana Pia; Rizzi, Daniele; Signoriello, Giuseppe; Sibilia, Maria; Ciardiello, Fortunato; Martinelli, Erika.

In: Molecular Cancer Therapeutics, Vol. 18, No. 4, 04.2019, p. 845-855.

Research output: Contribution to journalArticle

Martini, G, Cardone, C, Vitiello, PP, Belli, V, Napolitano, S, Troiani, T, Ciardiello, D, Della Corte, CM, Morgillo, F, Matrone, N, Sforza, V, Papaccio, G, Desiderio, V, Paul, MC, Moreno-Viedma, V, Normanno, N, Rachiglio, AM, Tirino, V, Maiello, E, Latiano, TP, Rizzi, D, Signoriello, G, Sibilia, M, Ciardiello, F & Martinelli, E 2019, 'EPHA2 Is a Predictive Biomarker of Resistance and a Potential Therapeutic Target for Improving Antiepidermal Growth Factor Receptor Therapy in Colorectal Cancer', Molecular Cancer Therapeutics, vol. 18, no. 4, pp. 845-855. https://doi.org/10.1158/1535-7163.MCT-18-0539
Martini, Giulia ; Cardone, Claudia ; Vitiello, Pietro Paolo ; Belli, Valentina ; Napolitano, Stefania ; Troiani, Teresa ; Ciardiello, Davide ; Della Corte, Carminia Maria ; Morgillo, Floriana ; Matrone, Nunzia ; Sforza, Vincenzo ; Papaccio, Gianpaolo ; Desiderio, Vincenzo ; Paul, Mariel C ; Moreno-Viedma, Veronica ; Normanno, Nicola ; Rachiglio, Anna Maria ; Tirino, Virginia ; Maiello, Evaristo ; Latiano, Tiziana Pia ; Rizzi, Daniele ; Signoriello, Giuseppe ; Sibilia, Maria ; Ciardiello, Fortunato ; Martinelli, Erika. / EPHA2 Is a Predictive Biomarker of Resistance and a Potential Therapeutic Target for Improving Antiepidermal Growth Factor Receptor Therapy in Colorectal Cancer. In: Molecular Cancer Therapeutics. 2019 ; Vol. 18, No. 4. pp. 845-855.
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abstract = "The EPHA2 tyrosine kinase receptor is implicated in tumor progression and targeted therapies resistance. We evaluated EPHA2 as a potential resistance marker to the antiepidermal growth factor receptor (EGFR) monoclonal antibody cetuximab in colorectal cancer. We studied activation of EPHA2 in a panel of human colorectal cancer cell lines sensitive or resistant to anti-EGFR drugs. The in vitro and in vivo effects of ALW-II-41-27 (an EPHA2 inhibitor) and/or cetuximab treatment were tested. Formalin-fixed paraffin-embedded tumor specimens from 82 RAS wild-type (WT) metastatic colorectal cancer patients treated with FOLFIRI + cetuximab as first-line therapy in the CAPRI-GOIM trial were assessed for EPHA2 expression by immunohistochemistry and correlated with treatment efficacy. EPHA2 was differentially activated in colorectal cancer cell lines. Combined treatment with ALW-II-41-27 plus cetuximab reverted primary and acquired resistance to cetuximab, causing cell growth inhibition, inducing apoptosis and cell-cycle G1-G2 arrest. In tumor xenograft models, upon progression to cetuximab, ALW-II-41-27 addition significantly inhibited tumor growth. EPHA2 protein expression was detected in 55 of 82 tumor samples, frequently expressed in less-differentiated and left-sided tumors. High levels of EPHA2 significantly correlated with worse progression-free survival [8.6 months; confidence interval (CI) 95{\%}, 6.4-10.8; vs. 12.3 months; CI 95{\%}, 10.4-14.2; P = 0.03] and with increased progression rate (29{\%} vs. 9{\%}, P = 0.02). A specific EPHA2 inhibitor reverts in vitro and in vivo primary and acquired resistance to anti-EGFR therapy. EPHA2 levels are significantly associated with worse outcome in patients treated with FOLFIRI + cetuximab. These results highlight EPHA2 as a potential therapeutic target in metastatic colorectal cancer.",
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AU - Martini, Giulia

AU - Cardone, Claudia

AU - Vitiello, Pietro Paolo

AU - Belli, Valentina

AU - Napolitano, Stefania

AU - Troiani, Teresa

AU - Ciardiello, Davide

AU - Della Corte, Carminia Maria

AU - Morgillo, Floriana

AU - Matrone, Nunzia

AU - Sforza, Vincenzo

AU - Papaccio, Gianpaolo

AU - Desiderio, Vincenzo

AU - Paul, Mariel C

AU - Moreno-Viedma, Veronica

AU - Normanno, Nicola

AU - Rachiglio, Anna Maria

AU - Tirino, Virginia

AU - Maiello, Evaristo

AU - Latiano, Tiziana Pia

AU - Rizzi, Daniele

AU - Signoriello, Giuseppe

AU - Sibilia, Maria

AU - Ciardiello, Fortunato

AU - Martinelli, Erika

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AB - The EPHA2 tyrosine kinase receptor is implicated in tumor progression and targeted therapies resistance. We evaluated EPHA2 as a potential resistance marker to the antiepidermal growth factor receptor (EGFR) monoclonal antibody cetuximab in colorectal cancer. We studied activation of EPHA2 in a panel of human colorectal cancer cell lines sensitive or resistant to anti-EGFR drugs. The in vitro and in vivo effects of ALW-II-41-27 (an EPHA2 inhibitor) and/or cetuximab treatment were tested. Formalin-fixed paraffin-embedded tumor specimens from 82 RAS wild-type (WT) metastatic colorectal cancer patients treated with FOLFIRI + cetuximab as first-line therapy in the CAPRI-GOIM trial were assessed for EPHA2 expression by immunohistochemistry and correlated with treatment efficacy. EPHA2 was differentially activated in colorectal cancer cell lines. Combined treatment with ALW-II-41-27 plus cetuximab reverted primary and acquired resistance to cetuximab, causing cell growth inhibition, inducing apoptosis and cell-cycle G1-G2 arrest. In tumor xenograft models, upon progression to cetuximab, ALW-II-41-27 addition significantly inhibited tumor growth. EPHA2 protein expression was detected in 55 of 82 tumor samples, frequently expressed in less-differentiated and left-sided tumors. High levels of EPHA2 significantly correlated with worse progression-free survival [8.6 months; confidence interval (CI) 95%, 6.4-10.8; vs. 12.3 months; CI 95%, 10.4-14.2; P = 0.03] and with increased progression rate (29% vs. 9%, P = 0.02). A specific EPHA2 inhibitor reverts in vitro and in vivo primary and acquired resistance to anti-EGFR therapy. EPHA2 levels are significantly associated with worse outcome in patients treated with FOLFIRI + cetuximab. These results highlight EPHA2 as a potential therapeutic target in metastatic colorectal cancer.

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