期刊
BRITISH JOURNAL OF CANCER
卷 113, 期 12, 页码 1730-1734出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/bjc.2015.401
关键词
entrectinib; gene fusions; colorectal cancer; CAD-ALK; ALK
类别
资金
- Fondazione Oncologia Niguarda Onlus, grant Terapia Molecolare dei Tumori
- Associazione Italiana Ricerca Cancro (AIRC), grant 2010-2015 Special Program Molecular Clinical Oncology 5 x 1000 project [9970]
- European Union 7th Framework Programme, COLTHERES [259015]
- Community Research and Development Information Service (CORDIS), MoTriColor (Molecularly guided trials with specific treatment strategies in patients with advanced newly molecular defined subtypes of colorectal cancer) [635342]
Background: Activated anaplastic lymphoma kinase (ALK) gene fusions are recurrent events in a small fraction of colorectal cancers (CRCs), although these events have not yet been exploited as in other malignancies. Methods: We detected ALK protein expression by immunohistochemistry and gene rearrangements by fluorescence in situ hybridisation in the ALKA-372-001 phase I study of the pan-Trk, ROS1, and ALK inhibitor entrectinib. One out of 487 CRCs showed ALK positivity with a peculiar pattern that prompted further characterisation by targeted sequencing using anchored multiplex PCR. Results: A novel ALK fusion with the carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD) gene (CAD-ALK fusion gene) was identified. It resulted from inversion within chromosome 2 and the fusion of exons 1-35 of CAD with exons 20-29 of ALK. After failure of previous standard therapies, treatment of this patient with the ALK inhibitor entrectinib resulted in a durable objective tumour response. Conclusions: We describe the novel CAD-ALK rearrangement as an oncogene and provide the first evidence of its drugability as a new molecular target in CRC.
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