Background: Combined MET and BRAF inhibition showed clinical benefit in a patient with rectal cancer carrying BRAFV600E and MET amplification. However after 4 months, acquired resistance emerged and the patient deceased shortly after disease progression. The mechanism of resistance to this drug combination is unknown. Methods: We analysed plasma circulating tumour DNA obtained at progression by exome sequencing and digital PCR. MET gene and mRNA in situ hybridisation analyses in two bioptic specimens obtained at progression were used to confirm the plasma data. Results: We identified in plasma MET gene hyper-amplification as a potential mechanism underlying therapy resistance. Increased MET gene copy and transcript levels were detected in liver and lymph node metastatic biopsies. Finally, transduction of MET in BRAF mutant colorectal cancer cells conferred refractoriness to BRAF and MET inhibition. Conclusions: We identified in a rectal cancer patient MET gene hyper-amplification as mechanism of resistance to dual BRAF and MET inhibition.
Emergence of MET hyper-amplification at progression to MET and BRAF inhibition in colorectal cancer / D. Oddo, G. Siravegna, A. Gloghini, C. Vernieri, B. Mussolin, F. Morano, G. Crisafulli, R. Berenato, G. Corti, C.C. Volpi, M. Buscarino, M. Niger, P.D. Dunne, G. Rospo, E. Valtorta, A. Bartolini, G. Fucà, S. Lamba, A. Martinetti, M. Di Bartolomeo, F. De Braud, A. Bardelli, F. Pietrantonio, F. Di Nicolantonio. - In: BRITISH JOURNAL OF CANCER. - ISSN 1532-1827. - 117:3(2017 Jul 25), pp. 347-352.
|Titolo:||Emergence of MET hyper-amplification at progression to MET and BRAF inhibition in colorectal cancer|
|Parole Chiave:||antineoplastic combined chemotherapy protocols; cell line; DNA, neoplasm; disease progression; drug resistance, neoplasm; fatal outcome; gene amplification; humans; indoles; middle aged; proto-oncogene proteins B-raf; proto-oncogene proteins C-met; pyrazoles; pyridines; rectal neoplasms; sulfonamides; oncology; cancer research|
|Settore Scientifico Disciplinare:||Settore MED/06 - Oncologia Medica|
|Data di pubblicazione:||25-lug-2017|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1038/bjc.2017.196|
|Appare nelle tipologie:||01 - Articolo su periodico|