Integrated genomic characterization reveals novel, therapeutically relevant drug targets in FGFR and EGFR pathways in sporadic intrahepatic cholangiocarcinoma.

Autor:	Borad MJ; Division of Hematology/Oncology Mayo Clinic, Scottsdale, Arizona, United States of America ; Mayo Clinic Cancer Center, Scottsdale, Arizona, United States of America ; Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, United States of America., Champion MD; Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, United States of America ; Department of Biomedical Statistics and Informatics, Mayo Clinic, Scottsdale, Arizona, United States of America., Egan JB; Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, United States of America., Liang WS; Translational Genomics Research Institute, Phoenix, Arizona, United States of America., Fonseca R; Division of Hematology/Oncology Mayo Clinic, Scottsdale, Arizona, United States of America ; Mayo Clinic Cancer Center, Scottsdale, Arizona, United States of America ; Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, United States of America., Bryce AH; Division of Hematology/Oncology Mayo Clinic, Scottsdale, Arizona, United States of America ; Mayo Clinic Cancer Center, Scottsdale, Arizona, United States of America ; Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, United States of America., McCullough AE; Department of Pathology, Mayo Clinic, Scottsdale, Arizona, United States of America., Barrett MT; Mayo Clinic Cancer Center, Scottsdale, Arizona, United States of America ; Translational Genomics Research Institute, Phoenix, Arizona, United States of America., Hunt K; Division of Hematology/Oncology Mayo Clinic, Scottsdale, Arizona, United States of America., Patel MD; Department of Radiology, Mayo Clinic, Scottsdale, Arizona, United States of America., Young SW; Department of Radiology, Mayo Clinic, Scottsdale, Arizona, United States of America., Collins JM; Department of Radiology, Mayo Clinic, Scottsdale, Arizona, United States of America., Silva AC; Department of Radiology, Mayo Clinic, Scottsdale, Arizona, United States of America., Condjella RM; Mayo Clinic Cancer Center, Scottsdale, Arizona, United States of America., Block M; Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, United States of America ; Mayo Clinic Cancer Center, Rochester, Minnesota, United States of America., McWilliams RR; Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, United States of America ; Mayo Clinic Cancer Center, Rochester, Minnesota, United States of America., Lazaridis KN; Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, United States of America., Klee EW; Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, United States of America ; Department of Biomedical Statistics and Informatics, Mayo Clinic, Scottsdale, Arizona, United States of America., Bible KC; Mayo Clinic Cancer Center, Rochester, Minnesota, United States of America., Harris P; Investigational Drug Branch, National Cancer Institute, Rockville, Maryland, United States of America., Oliver GR; Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, United States of America ; Department of Biomedical Statistics and Informatics, Mayo Clinic, Scottsdale, Arizona, United States of America., Bhavsar JD; Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, United States of America ; Department of Biomedical Statistics and Informatics, Mayo Clinic, Scottsdale, Arizona, United States of America., Nair AA; Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, United States of America ; Department of Biomedical Statistics and Informatics, Mayo Clinic, Scottsdale, Arizona, United States of America., Middha S; Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, United States of America ; Department of Biomedical Statistics and Informatics, Mayo Clinic, Scottsdale, Arizona, United States of America., Asmann Y; Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, United States of America ; Department of Biomedical Statistics and Informatics, Mayo Clinic, Scottsdale, Arizona, United States of America., Kocher JP; Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, United States of America ; Department of Biomedical Statistics and Informatics, Mayo Clinic, Scottsdale, Arizona, United States of America., Schahl K; Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, United States of America., Kipp BR; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States of America., Barr Fritcher EG; Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States of America., Baker A; Translational Genomics Research Institute, Phoenix, Arizona, United States of America., Aldrich J; Translational Genomics Research Institute, Phoenix, Arizona, United States of America., Kurdoglu A; Translational Genomics Research Institute, Phoenix, Arizona, United States of America., Izatt T; Translational Genomics Research Institute, Phoenix, Arizona, United States of America., Christoforides A; Translational Genomics Research Institute, Phoenix, Arizona, United States of America., Cherni I; Translational Genomics Research Institute, Phoenix, Arizona, United States of America., Nasser S; Translational Genomics Research Institute, Phoenix, Arizona, United States of America., Reiman R; Translational Genomics Research Institute, Phoenix, Arizona, United States of America., Phillips L; Translational Genomics Research Institute, Phoenix, Arizona, United States of America., McDonald J; Translational Genomics Research Institute, Phoenix, Arizona, United States of America., Adkins J; Translational Genomics Research Institute, Phoenix, Arizona, United States of America., Mastrian SD; Translational Genomics Research Institute, Phoenix, Arizona, United States of America., Placek P; Translational Genomics Research Institute, Phoenix, Arizona, United States of America., Watanabe AT; Translational Genomics Research Institute, Phoenix, Arizona, United States of America., Lobello J; Translational Genomics Research Institute, Phoenix, Arizona, United States of America., Han H; Translational Genomics Research Institute, Phoenix, Arizona, United States of America., Von Hoff D; Mayo Clinic Cancer Center, Scottsdale, Arizona, United States of America ; Translational Genomics Research Institute, Phoenix, Arizona, United States of America., Craig DW; Translational Genomics Research Institute, Phoenix, Arizona, United States of America., Stewart AK; Division of Hematology/Oncology Mayo Clinic, Scottsdale, Arizona, United States of America ; Mayo Clinic Cancer Center, Scottsdale, Arizona, United States of America ; Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, United States of America., Carpten JD; Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
Jazyk:	angličtina
Zdroj:	PLoS genetics [PLoS Genet] 2014 Feb 13; Vol. 10 (2), pp. e1004135. Date of Electronic Publication: 2014 Feb 13 (Print Publication: 2014).
DOI:	10.1371/journal.pgen.1004135
Abstrakt:	Advanced cholangiocarcinoma continues to harbor a difficult prognosis and therapeutic options have been limited. During the course of a clinical trial of whole genomic sequencing seeking druggable targets, we examined six patients with advanced cholangiocarcinoma. Integrated genome-wide and whole transcriptome sequence analyses were performed on tumors from six patients with advanced, sporadic intrahepatic cholangiocarcinoma (SIC) to identify potential therapeutically actionable events. Among the somatic events captured in our analysis, we uncovered two novel therapeutically relevant genomic contexts that when acted upon, resulted in preliminary evidence of anti-tumor activity. Genome-wide structural analysis of sequence data revealed recurrent translocation events involving the FGFR2 locus in three of six assessed patients. These observations and supporting evidence triggered the use of FGFR inhibitors in these patients. In one example, preliminary anti-tumor activity of pazopanib (in vitro FGFR2 IC50≈350 nM) was noted in a patient with an FGFR2-TACC3 fusion. After progression on pazopanib, the same patient also had stable disease on ponatinib, a pan-FGFR inhibitor (in vitro, FGFR2 IC50≈8 nM). In an independent non-FGFR2 translocation patient, exome and transcriptome analysis revealed an allele specific somatic nonsense mutation (E384X) in ERRFI1, a direct negative regulator of EGFR activation. Rapid and robust disease regression was noted in this ERRFI1 inactivated tumor when treated with erlotinib, an EGFR kinase inhibitor. FGFR2 fusions and ERRFI mutations may represent novel targets in sporadic intrahepatic cholangiocarcinoma and trials should be characterized in larger cohorts of patients with these aberrations.
Databáze:	MEDLINE
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