Integrated Genomic Characterization Reveals Novel, Therapeutically Relevant Drug Targets in FGFR and EGFR Pathways in Sporadic Intrahepatic Cholangiocarcinoma

• DOI: 10.1371/journal.pgen.1004135
• Publication Date: 2014-02-13T21:52:03Z
• Authors: Mitesh J. Borad; Mia D. Champion; Jan B. Egan; Winnie S. Liang; Rafael Fonseca; Alan H. Bryce; Ann E. McCullough; Michael T. Barrett; Katherine Hunt; Maitray D. Patel; Scott W. Young; Joseph M. Collins; Alvin C. Silva; Rachel M. Condjella; Matthew Block; Robert R. McWilliams; Konstantinos N. L...; Eric W. Klee; Keith C. Bible; Pamela Harris; Gavin R. Oliver; Jaysheel D. Bhavsar; Asha A. Nair; Sumit Middha; Yan Asmann; Jean-Pierre Kocher; Kimberly Schahl; Benjamin R. Kipp; Emily G. Barr Fri...; Angela Baker; Jessica Aldrich; Ahmet Kurdoglu; Tyler Izatt; Alexis Christofor...; Irene Cherni; Sara Nasser; Rebecca Reiman; Lori Phillips; Jackie McDonald; Jonathan Adkins; Stephen D. Mastrian; Pamela Placek; Aprill T. Watanabe; Janine LoBello; Haiyong Han; Daniel Von Hoff; David W. Craig; A. Keith Stewart; John D. Carpten
• Keywords: Pazopanib; Ponatinib; Intrahepatic Cholangiocarcinoma; Exome

Advanced cholangiocarcinoma continues to harbor a difficult prognosis and therapeutic options have been limited. During the course of clinical trial whole genomic sequencing seeking druggable targets, we examined six patients with advanced cholangiocarcinoma. Integrated genome-wide transcriptome sequence analyses were performed on tumors from advanced, sporadic intrahepatic (SIC) identify potential therapeutically actionable events. Among somatic events captured in our analysis, uncovered two novel relevant contexts that when acted upon, resulted preliminary evidence anti-tumor activity. Genome-wide structural analysis data revealed recurrent translocation involving FGFR2 locus three assessed patients. These observations supporting triggered use FGFR inhibitors these In one example, activity pazopanib (in vitro IC50≈350 nM) was noted patient an FGFR2-TACC3 fusion. After progression pazopanib, same also had stable disease ponatinib, pan-FGFR inhibitor vitro, IC50≈8 nM). independent non-FGFR2 patient, exome allele specific nonsense mutation (E384X) ERRFI1, direct negative regulator EGFR activation. Rapid robust regression this ERRFI1 inactivated tumor treated erlotinib, kinase inhibitor. fusions ERRFI mutations may represent targets trials should be characterized larger cohorts aberrations.