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

PLoS Genet 2014 Feb 13;10(2):e1004135. Epub 2014 Feb 13.

Translational Genomics Research Institute, Phoenix, Arizona, United States of America.

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.

Download full-text PDF

Source Listing
February 2014
58 Reads
69 Citations

Publication Analysis

Top Keywords

intrahepatic cholangiocarcinoma
sporadic intrahepatic
therapeutically relevant
anti-tumor activity
advanced cholangiocarcinoma
patients advanced
vitro fgfr2
novel therapeutically
preliminary evidence
fgfr2 ic50≈350
ic50≈350 patient
patient fgfr2-tacc3
pazopanib vitro
activity pazopanib
inhibitors patients
patients example
example preliminary
preliminary anti-tumor


(Supplied by CrossRef)
Cholangiocarcinoma in patients with opisthorchiasis
P Watanapa et al.
The British journal of surgery 1996
Liver fluke-associated cholangiocarcinoma
P Watanapa et al.
The British journal of surgery 2002
Incidence and risk factors for cholangiocarcinoma in primary sclerosing cholangitis
K Burak et al.
The American journal of gastroenterology 2004
High lifetime risk of cancer in primary sclerosing cholangitis
MM Claessen et al.
Journal of hepatology 2009
Congenital choledochal cysts in adults
BC Visser et al.
Archives of surgery 2004
Hepatitis B and C virus infection and the risk of biliary tract cancer: a population-based study in China
AW Hsing et al.
International journal of cancer Journal international du cancer 2008
Pathogenesis of cholangiocarcinoma in the porta hepatis and infection of hepatitis virus
XF Liu et al.
Hepatobiliary & pancreatic diseases international : HBPD INT 2003

Similar Publications