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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.

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Acknowledgements

We thank all our colleagues for helpful scientific discussion; Drs Martinoglio, Porporato and Buscarino for technical support with RT–PCR and sequencing; Dr Perra for tumor microdissection; Dr Giove for support with immunohistochemistry; animal facility employees; Dr Natale for critical manuscript reading. SG and SC are EuroPDX Consortium members. This work was funded by the Italian Association for Cancer Research (AIRC); IG grant 15464 to SG and Fondazione Piemontese per la Ricerca sul Cancro (ONLUS) 5 X 1000 Fondi Ministero della Salute 2013.

Author contributions

SG and SC conceived the study; SG, SC, MA, S Marsoni and PMC contributed to design the experiments; MDS provided the patient material, MA, CM, TC, S Menegon and MC performed experiments; MD contributed to mouse surgery; A Sapino, PC, IS performed the pathologic analysis; LC performed FISH analysis; A Sottile performed the blood biochemical analyses; SG, SC and MA wrote the manuscript. All authors revised the manuscript.

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Correspondence to S Corso or S Giordano.

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Apicella, M., Migliore, C., Capelôa, T. et al. Dual MET/EGFR therapy leads to complete response and resistance prevention in a MET-amplified gastroesophageal xenopatient cohort. Oncogene 36, 1200–1210 (2017). https://doi.org/10.1038/onc.2016.283

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