title: Integrated genomic characterization reveals novel, therapeutically relevant drug targets in FGFR and EGFR pathways in sporadic intrahepatic cholangiocarcinoma.
abstract: 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.
authors.affiliation: 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.
authors.forename: Mitesh J
authors.initials: MJ
authors.lastname: Borad
authors.affiliation: 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.
authors.forename: Mia D
authors.initials: MD
authors.lastname: Champion
authors.affiliation: Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Jan B
authors.initials: JB
authors.lastname: Egan
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
authors.forename: Winnie S
authors.initials: WS
authors.lastname: Liang
authors.affiliation: 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.
authors.forename: Rafael
authors.initials: R
authors.lastname: Fonseca
authors.affiliation: 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.
authors.forename: Alan H
authors.initials: AH
authors.lastname: Bryce
authors.affiliation: Department of Pathology, Mayo Clinic, Scottsdale, Arizona, United States of America.
authors.forename: Ann E
authors.initials: AE
authors.lastname: McCullough
authors.affiliation: Mayo Clinic Cancer Center, Scottsdale, Arizona, United States of America ; Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Barrett
authors.affiliation: Division of Hematology/Oncology Mayo Clinic, Scottsdale, Arizona, United States of America.
authors.forename: Katherine
authors.initials: K
authors.lastname: Hunt
authors.affiliation: Department of Radiology, Mayo Clinic, Scottsdale, Arizona, United States of America.
authors.forename: Maitray D
authors.initials: MD
authors.lastname: Patel
authors.affiliation: Department of Radiology, Mayo Clinic, Scottsdale, Arizona, United States of America.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Young
authors.affiliation: Department of Radiology, Mayo Clinic, Scottsdale, Arizona, United States of America.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Collins
authors.affiliation: Department of Radiology, Mayo Clinic, Scottsdale, Arizona, United States of America.
authors.forename: Alvin C
authors.initials: AC
authors.lastname: Silva
authors.affiliation: Mayo Clinic Cancer Center, Scottsdale, Arizona, United States of America.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Condjella
authors.affiliation: Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, United States of America ; Mayo Clinic Cancer Center, Rochester, Minnesota, United States of America.
authors.forename: Matthew
authors.initials: M
authors.lastname: Block
authors.affiliation: Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, United States of America ; Mayo Clinic Cancer Center, Rochester, Minnesota, United States of America.
authors.forename: Robert R
authors.initials: RR
authors.lastname: McWilliams
authors.affiliation: Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Konstantinos N
authors.initials: KN
authors.lastname: Lazaridis
authors.affiliation: 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.
authors.forename: Eric W
authors.initials: EW
authors.lastname: Klee
authors.affiliation: Mayo Clinic Cancer Center, Rochester, Minnesota, United States of America.
authors.forename: Keith C
authors.initials: KC
authors.lastname: Bible
authors.affiliation: Investigational Drug Branch, National Cancer Institute, Rockville, Maryland, United States of America.
authors.forename: Pamela
authors.initials: P
authors.lastname: Harris
authors.affiliation: 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.
authors.forename: Gavin R
authors.initials: GR
authors.lastname: Oliver
authors.affiliation: 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.
authors.forename: Jaysheel D
authors.initials: JD
authors.lastname: Bhavsar
authors.affiliation: 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.
authors.forename: Asha A
authors.initials: AA
authors.lastname: Nair
authors.affiliation: 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.
authors.forename: Sumit
authors.initials: S
authors.lastname: Middha
authors.affiliation: 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.
authors.forename: Yan
authors.initials: Y
authors.lastname: Asmann
authors.affiliation: 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.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Kocher
authors.affiliation: Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Schahl
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Kipp
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States of America.
authors.forename: Emily G
authors.initials: EG
authors.lastname: Barr Fritcher
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
authors.forename: Angela
authors.initials: A
authors.lastname: Baker
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
authors.forename: Jessica
authors.initials: J
authors.lastname: Aldrich
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Kurdoglu
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
authors.forename: Tyler
authors.initials: T
authors.lastname: Izatt
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
authors.forename: Alexis
authors.initials: A
authors.lastname: Christoforides
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
authors.forename: Irene
authors.initials: I
authors.lastname: Cherni
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
authors.forename: Sara
authors.initials: S
authors.lastname: Nasser
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Reiman
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
authors.forename: Lori
authors.initials: L
authors.lastname: Phillips
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
authors.forename: Jackie
authors.initials: J
authors.lastname: McDonald
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Adkins
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Mastrian
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
authors.forename: Pamela
authors.initials: P
authors.lastname: Placek
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
authors.forename: Aprill T
authors.initials: AT
authors.lastname: Watanabe
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
authors.forename: Janine
authors.initials: J
authors.lastname: Lobello
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
authors.forename: Haiyong
authors.initials: H
authors.lastname: Han
authors.affiliation: Mayo Clinic Cancer Center, Scottsdale, Arizona, United States of America ; Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
authors.forename: Daniel
authors.initials: D
authors.lastname: Von Hoff
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
authors.forename: David W
authors.initials: DW
authors.lastname: Craig
authors.affiliation: 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.
authors.forename: A Keith
authors.initials: AK
authors.lastname: Stewart
authors.affiliation: Translational Genomics Research Institute, Phoenix, Arizona, United States of America.
authors.forename: John D
authors.initials: JD
authors.lastname: Carpten
mesh_terms: D001650:Bile Duct Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000473:pathology; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride; D015894:Genome, Human; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage; D007191:Indazoles; D058990:Molecular Targeted Therapy; D009154:Mutation; D011379:Prognosis; D047428:Protein Kinase Inhibitors; D011724:Pyridazines / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D011799:Quinazolines / Q000008:administration & dosage; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D013449:Sulfonamides / Q000008:administration & dosage; D059467:Transcriptome
chemical_list: D007093:Imidazoles; D007191:Indazoles; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D011743:Pyrimidines; D011799:Quinazolines; D013449:Sulfonamides; C545373:ponatinib; C516667:pazopanib; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2