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  • Title: Novel CAD-ALK gene rearrangement is drugable by entrectinib in colorectal cancer.
    Author: Amatu A, Somaschini A, Cerea G, Bosotti R, Valtorta E, Buonandi P, Marrapese G, Veronese S, Luo D, Hornby Z, Multani P, Murphy D, Shoemaker R, Lauricella C, Giannetta L, Maiolani M, Vanzulli A, Ardini E, Galvani A, Isacchi A, Sartore-Bianchi A, Siena S.
    Journal: Br J Cancer; 2015 Dec 22; 113(12):1730-4. PubMed ID: 26633560.
    Abstract:
    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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