title: Dual MET/EGFR therapy leads to complete response and resistance prevention in a MET-amplified gastroesophageal xenopatient cohort.
abstract: 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.
authors.affiliation: Department of Oncology, University of Torino, Candiolo, Italy.|Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Apicella
authors.affiliation: Department of Oncology, University of Torino, Candiolo, Italy.|Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Migliore
authors.affiliation: Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Italy.|Department of Clinical and Biological Sciences, University of Torino, Orbassano, Italy.
authors.forename: T
authors.initials: T
authors.lastname: Capelôa
authors.affiliation: Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Menegon
authors.affiliation: Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Cargnelutti
authors.affiliation: Department of Surgery, Ospedale Molinette, Torino, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Degiuli
authors.affiliation: Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Italy.|Department of Medical Science, University of Torino, Torino, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Sapino
authors.affiliation: Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Sottile
authors.affiliation: Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Sarotto
authors.affiliation: Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Casorzo
authors.affiliation: Department of Medical Science, University of Torino, Torino, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Cassoni
authors.affiliation: Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Italy.
authors.forename: M
authors.initials: M
authors.lastname: De Simone
authors.affiliation: Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Italy.
authors.forename: P M
authors.initials: PM
authors.lastname: Comoglio
authors.affiliation: Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Marsoni
authors.affiliation: Department of Oncology, University of Torino, Candiolo, Italy.|Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Corso
authors.affiliation: Department of Oncology, University of Torino, Candiolo, Italy.|Candiolo Cancer Institute - FPO, IRCCS, Candiolo, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Giordano
mesh_terms: D000369:Aged, 80 and over; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D000068818:Cetuximab / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004943:Esophagogastric Junction / Q000187:drug effects; D005784:Gene Amplification; D006801:Humans; D000077341:Lapatinib; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010766:Phosphorylation; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000008:administration & dosage; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D011799:Quinazolines; D000077341:Lapatinib; C512478:EGFR protein, human; D066246:ErbB Receptors; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D000068818:Cetuximab