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

  • Mol Cancer Ther. 2019 Apr;18(4):845-855. doi: 10.1158/1535-7163.MCT-18-0539.
Giulia Martini  1 ,  Claudia Cardone  1 ,  Pietro Paolo Vitiello  1 ,  Valentina Belli  1 ,  Stefania Napolitano  1 ,  Teresa Troiani  1 ,  Davide Ciardiello  1 ,  Carminia Maria Della Corte  1 ,  Floriana Morgillo  1 ,  Nunzia Matrone  1 ,  Vincenzo Sforza  2 ,  Gianpaolo Papaccio  3 ,  Vincenzo Desiderio  3 ,  Mariel C Paul  4 ,  Veronica Moreno-Viedma  4 ,  Nicola Normanno  5 ,  Anna Maria Rachiglio  5 ,  Virginia Tirino  3 ,  Evaristo Maiello  6 ,  Tiziana Pia Latiano  6 ,  Daniele Rizzi  6 ,  Giuseppe Signoriello  7 ,  Maria Sibilia  4 ,  Fortunato Ciardiello  8 ,  Erika Martinelli  8
Affiliations
  • 1. Medical Oncology, Department of Precision Medicine, Università degli Studi della Campania L. Vanvitelli, Naples, Italy.
  • 2. Department of Clinical Experimental Thoracic Oncology, Istituto Nazionale Tumori, IRCCS, Fondazione Pascale, Naples, Italy.
  • 3. Department of Experimental Medicine, Università degli Studi della Campania Luigi Vanvitelli Napoli, IT, Naples, Italy.
  • 4. Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, Vienna, Austria.
  • 5. Cell Biology and Biotherapy Unit, Istituto Nazionale Tumori, IRCCS, Fondazione Pascale, Naples, Italy.
  • 6. Medical Oncology, Hospital Casa Sollievo Della Sofferenza-San Giovanni Rotondo (Foggia), San Giovanni Rotondo, Italy.
  • 7. Biostatistics, Dipartimento di Salute Mentale e Fisica e Medicina Preventiva, Università degli Studi della Campania L. Vanvitelli, Naples, Italy.
  • 8. Medical Oncology, Department of Precision Medicine, Università degli Studi della Campania L. Vanvitelli, Naples, Italy. [email protected] [email protected].
PMID: 30824612 DOI: 10.1158/1535-7163.MCT-18-0539
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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