Oddo Daniele, Siravegna Giulia, Gloghini Annunziata, Vernieri Claudio, Mussolin Benedetta, Morano Federica, Crisafulli Giovanni, Berenato Rosa, Corti Giorgio, Volpi Chiara Costanza, Buscarino Michela, Niger Monica, Dunne Philip D, Rospo Giuseppe, Valtorta Emanuele, Bartolini Alice, Fucà Giovanni, Lamba Simona, Martinetti Antonia, Di Bartolomeo Maria, de Braud Filippo, Bardelli Alberto, Pietrantonio Filippo, Di Nicolantonio Federica
Department of Oncology, University of Torino, Candiolo (TO) 10060, Italy.
Candiolo Cancer Institute-FPO, IRCCS, Candiolo (TO) 10060, Italy.
Br J Cancer. 2017 Jul 25;117(3):347-352. doi: 10.1038/bjc.2017.196. Epub 2017 Jun 27.
Combined MET and BRAF inhibition showed clinical benefit in a patient with rectal cancer carrying BRAF 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.
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.
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.
We identified in a rectal cancer patient MET gene hyper-amplification as mechanism of resistance to dual BRAF and MET inhibition.
联合使用MET和BRAF抑制剂对一名携带BRAF和MET扩增的直肠癌患者显示出临床益处。然而，4个月后出现了获得性耐药，患者在疾病进展后不久死亡。这种联合用药的耐药机制尚不清楚。
我们通过外显子组测序和数字PCR分析了疾病进展时获得的血浆循环肿瘤DNA。对疾病进展时获得的两份活检标本进行MET基因和mRNA原位杂交分析，以确认血浆数据。
我们在血浆中鉴定出MET基因高度扩增是治疗耐药的潜在机制。在肝脏和淋巴结转移活检中检测到MET基因拷贝数和转录水平增加。最后，在BRAF突变的结肠癌细胞中导入MET可导致对BRAF和MET抑制产生耐药性。
我们在一名直肠癌患者中鉴定出MET基因高度扩增是对BRAF和MET双重抑制耐药的机制。
