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.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Drug Resistance, Neoplasm/genetics , ErbB Receptors/antagonists & inhibitors , Esophageal Neoplasms/drug therapy , Gene Amplification , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Stomach Neoplasms/drug therapy , Aged, 80 and over , Animals , Apoptosis/drug effects , Biomarkers, Tumor/genetics , Cell Proliferation/drug effects , Cetuximab/administration & dosage , Esophageal Neoplasms/genetics , Esophageal Neoplasms/pathology , Esophagogastric Junction/drug effects , Humans , Lapatinib , Male , Mice , Mice, Inbred NOD , Mice, SCID , Phosphorylation , Quinazolines/administration & dosage , Signal Transduction , Stomach Neoplasms/genetics , Stomach Neoplasms/pathology , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
Karyotypic analysis of a gastric stromal tumor with the histologic and immunohistochemical features of a malignant, uncommitted lesion revealed clonal monosomies of chromosomes 14 and 22. Such changes, together with loss of chromosomes 15 and 18, as well as structural rearrangements involved chromosome 1, have been previously reported in gastrointestinal stromal tumors with smooth muscle differentiation. We suggest that monosomies of chromosomes 14 and 22 are early events in the malignant transformation of the mesenchymal cell-originating gastrointestinal stromal tumors.
Subject(s)
Monosomy , Stomach Neoplasms/genetics , Antigens, CD34/analysis , Chromosomes, Human, Pair 14 , Chromosomes, Human, Pair 22 , Humans , Karyotyping , Male , Middle Aged , Stomach Neoplasms/pathology , Stromal Cells , Vimentin/analysisABSTRACT
A case of a small cell malignant tumor that occurred in the soft tissues of a 16-year-old boy with Down syndrome (47,XY,+21) is reported. The histologic and histochemical patterns were consistent with an extraskeletal Ewing's sarcoma (ES). The cytogenetic analysis of the tumor cells showed a t(11;22)(q24;q21), tetrasomy of chromosome 21, and trisomy of chromosome 14. The observation of a t(11;22) in an ES gives credit to the morphologic evidence in favor of the common (probably neuroectodermal) origin of the skeletal and extraskeletal forms of Ewing's sarcoma (ES). The possible pathogenetic significance of the constitutional trisomy of chromosome 21 in determining the occurrence of this tumor is discussed.
