The EPHA2 tyrosine kinase receptor is implicated in tumor progression and targeted therapies resistance. We evaluated EPHA2 as potential resistance marker to the anti-epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab in colorectal cancer (CRC). We studied activation of EPHA2 in a panel of human CRC cell lines sensitive or resistant to anti-EGFR drugs. The in vitro and in vivo effects of ALW-II-41-27 (a EPHA2 inhibitor) and/or cetuximab treatment were tested. Formalin-fixed paraffin-embedded tumor specimens from 82 RAS wild type (WT) metastatic CRC 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 CRC 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 xenografts models, upon progression to cetuximab, ALW II-41-27 addition significantly inhibited tumor growth. EPHA2 protein expression was detected in 55/82 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 (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 CRC.

EPHA2 is a predictive biomarker of resistance and a potential therapeutic target for improving anti-epidermal growth factor receptor therapy in colorectal cancer

Martini, Giulia;Napolitano, Stefania;Troiani, Teresa;Della Corte, Carminia Maria;Morgillo, Floriana;Papaccio, Gianpaolo;Desiderio, Vincenzo;Tirino, Virginia;Signoriello, Giuseppe;Ciardiello, Fortunato;Martinelli, Erika
2019

Abstract

The EPHA2 tyrosine kinase receptor is implicated in tumor progression and targeted therapies resistance. We evaluated EPHA2 as potential resistance marker to the anti-epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab in colorectal cancer (CRC). We studied activation of EPHA2 in a panel of human CRC cell lines sensitive or resistant to anti-EGFR drugs. The in vitro and in vivo effects of ALW-II-41-27 (a EPHA2 inhibitor) and/or cetuximab treatment were tested. Formalin-fixed paraffin-embedded tumor specimens from 82 RAS wild type (WT) metastatic CRC 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 CRC 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 xenografts models, upon progression to cetuximab, ALW II-41-27 addition significantly inhibited tumor growth. EPHA2 protein expression was detected in 55/82 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 (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 CRC.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11591/404640
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