Dual MET/EGFR therapy leads to complete response and resistance prevention in a MET-amplified gastroesophageal xenopatient cohort

• Published in: Oncogene Vol. 36; no. 9; pp. 1200 - 1210
• Main Authors: Apicella, M, Migliore, C, Capelôa, T, Menegon, S, Cargnelutti, M, Degiuli, M, Sapino, A, Sottile, A, Sarotto, I, Casorzo, L, Cassoni, P, De Simone, M, Comoglio, P M, Marsoni, S, Corso, S, Giordano, S
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02-03-2017; Nature Publishing Group
• Subjects: 38/77; 631/67/1059/2326; 631/67/1059/602; 631/67/1504/1829; 631/67/70; 64/60; 82/51; Aged, 80 and over; Animals; Antimitotic agents; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apoptosis; Apoptosis - drug effects; Biomarkers, Tumor - genetics; c-Met protein; Cancer; Cancer therapies; Care and treatment; Cell Biology; Cell Proliferation - drug effects; Cetuximab - administration & dosage; Clinical trials; Diagnosis; Dosage and administration; Drug resistance; Drug Resistance, Neoplasm - genetics; Epidermal growth factor receptors; Esophageal cancer; Esophageal Neoplasms - drug therapy; Esophageal Neoplasms - genetics; Esophageal Neoplasms - pathology; Esophagogastric Junction - drug effects; Gastric cancer; Gene Amplification; Growth inhibition; Human Genetics; Humans; Internal Medicine; Male; Medicine; Medicine & Public Health; Mice; Mice, Inbred NOD; Mice, SCID; Oncology; original-article; Patient outcomes; Patients; Phosphorylation; Proto-Oncogene Proteins c-met - antagonists & inhibitors; Quinazolines - administration & dosage; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Risk factors; Signal Transduction; Stomach Neoplasms - drug therapy; Stomach Neoplasms - genetics; Stomach Neoplasms - pathology; Tumor Cells, Cultured; Tumors; Xenograft Model Antitumor Assays; Xenografts; Xenotransplantation; Italy
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2016.283

Amplification of the
MET
oncogene occurs in 2–4% of gastroesophageal cancers and defines a small and aggressive subset of tumors. Although
in vitro
studies have given very promising results, clinical trials with MET inhibitors have been disappointing, showing few and short lasting responses. The aim of the work was to exploit a
MET
-amplified patient-derived xenograft model to optimize anti-MET therapeutic strategies in gastroesophageal cancer. We found that despite the high
MET
amplification level (26 gene copies), in the absence of qualitative or quantitative alterations of EGFR, MET inhibitors induced only tumor growth inhibition, whereas dual MET/EGFR inhibition led to complete tumor regression. Importantly, the combo treatment completely prevented the onset of resistance, which quite rapidly appeared in tumors treated with MET monotherapy. We found that this secondary resistance was due to EGFR activation and could be overcome by dual MET/EGFR inhibition. Similar results were also obtained in a MET-addicted, established gastric cancer cell line.
In vitro
experiments performed on tumor-derived primary cells confirmed that MET inhibitors were not able to abrogate the activation of downstream transducers and that only the combined MET/EGFR treatment completely shut off the signaling. Previously reported cases, as well as those described here, showed only partial and transient sensitivity to anti-MET therapy. The finding that combined anti-MET/EGFR therapy—even in the absence of
EGFR
genetic alterations—induced complete and durable response, represents a proof of concept and guarantees further investigations, opening a new perspective of treatment for these patients.