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.

Massive parallel sequencing uncovers actionable FGFR2–PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma

“…FGFR fusion events have been recently identified in several cancers. Multiple partners have been discovered including BICC1, AFF3, CASP7 and CCDC6 among others [17][18][19][20] . These different partners play an important role in the control of enforced oligomerization and subsequent trans-autophosphorylation and activation of the tyrosine kinase gene involved in the rearrangement 12,17,21 .…”

“…19). Nonetheless, the incidence of FGFR2 fusions strikingly differs across the iCCA published cohorts, with a range between 50% in small series 17,18 to 10-15% in series of up to 96 patients 19,20,30 . Overall, our cohort consisted of Caucasian patients at early-intermediate stage iCCA amenable for resection, whereas other series mostly refer to Asian patients at more advanced stage of disease 19 .…”

“…NATURE COMMUNICATIONS | DOI: 10.1038/ncomms7087 ARTICLE described for FGFR2 and the reported fusions [17][18][19][20] appear to be the main mechanism of activation of this oncogene and could be explored for trial enrichment. 4 , as also seen in our study (10%).…”

“…In fact, one of such fusions (the EML-ALK fusion in lung cancer) has emerged as a druggable target and its inhibition leads to survival improvements 16 . Interestingly, a variety of FGFR2 gene fusions have been recently identified in iCCA [17][18][19][20] , suggesting that these events may represent novel candidate therapeutic targets and that similar strategies could be used for its clinical management.…”

Biliary cancer: intrahepatic cholangiocarcinoma vs. extrahepatic cholangiocarcinoma vs. gallbladder cancers: classification and therapeutic implications

“…These receptors bind to one of 18 secreted glycoprotein ligands, or fibroblast growth factors (FGFs), to their extracellular domain (71). Several FGFR2 chromosomal fusions, with several genomic partners, have been identified in IHCC (72)(73)(74)(75)(76)(77). Preclinical studies have identified several FGFR2 fusions (FGFR2-PPHLN1, FGFR2-BICC1, FGFR2-TACC3, AHCYL1) specifically in intrahepatic BC, where genomic sequencing identified an incidence ranging up to 50% of intrahepatic BC patients.…”