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

• Published in: Molecular cancer therapeutics Vol. 18; no. 4; pp. 845 - 855
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States 01.04.2019
• Subjects: Adult; Aged; Aged, 80 and over; Animals; Antineoplastic Agents, Immunological - administration & dosage; Antineoplastic Agents, Immunological - pharmacology; Antineoplastic Agents, Immunological - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Apoptosis - drug effects; Benzamides - pharmacology; Biomarkers, Tumor - metabolism; Camptothecin - analogs & derivatives; Camptothecin - therapeutic use; Cell Cycle Checkpoints - drug effects; Cell Line, Tumor; Cetuximab - administration & dosage; Cetuximab - pharmacology; Cetuximab - therapeutic use; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - pathology; Drug Resistance, Neoplasm; Ephrin-A2 - antagonists & inhibitors; Ephrin-A2 - metabolism; ErbB Receptors - antagonists & inhibitors; Female; Fluorouracil - therapeutic use; Humans; Leucovorin - therapeutic use; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Niacinamide - analogs & derivatives; Niacinamide - pharmacology; Progression-Free Survival; RNA Interference; Signal Transduction - drug effects; Transfection; Xenograft Model Antitumor Assays
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.mct-18-0539

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 and effects of ALW-II-41-27 (an EPHA2 inhibitor) and/or cetuximab treatment were tested. Formalin-fixed paraffin-embedded tumor specimens from 82 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; = 0.03] and with increased progression rate (29% vs. 9%, = 0.02). A specific EPHA2 inhibitor reverts and 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.