FGFR2Extracellular Domain In-Frame Deletions Are Therapeutically Targetable Genomic Alterations That Function as Oncogenic Drivers in Cholangiocarcinoma

Abstract

We conducted next generation DNA sequencing on 335 biliary tract cancers and characterized the genomic landscape by anatomic site within the biliary tree. In addition to frequent FGFR2 fusions among patients with intrahepatic cholangiocarcinoma (IHCC), we identified FGFR2 extracellular domain in-frame deletions (EIDs) in 5 of 178 (2.8%) patients with IHCC, including two patients with FGFR2 p.H167_N173del. Expression of this FGFR2 EID in NIH3T3 cells resulted in constitutive FGFR2 activation, oncogenic transformation, and sensitivity to FGFR inhibitors. Three patients with FGFR2 EIDs were treated with Debio 1347, an oral FGFR-1/2/3 inhibitor, and all showed partial responses. One patient developed an acquired L618F FGFR2 kinase domain mutation at disease progression and experienced a further partial response for 17 months to an irreversible FGFR2 inhibitor, futibatinib. Together, these findings reveal FGFR2 EIDs as an alternative mechanism of FGFR2 activation in IHCC that predict sensitivity to FGFR inhibitors in the clinic.Research.

In the literature: June 2021

“…The authors confirmed the importance of FRFR2 extracellular domain 'in-frame' deletions as oncogenic drivers in silico, in cell line models and in vivo and showed the ability of some FRGR inhibitors to block these activating signals. 7 Concerning clinical antitumor activity of FGFR inhibitors, partial responses were observed among these patients with FGFR2 extracellular domain in-frame deletions, comparing favorably with those reported for the different FGFR inhibitors in patients with IHCCs harboring FGFR2 fusions. These findings suggest that the degree of oncogenic addiction to FGFR2 may vary across these mutational contexts and support further clinical evaluation of FGFR inhibitors in patients with FGFR2 extracellular domain in-frame deletions.…”

Molecular Landscape and Therapeutic Strategies in Cholangiocarcinoma: An Integrated Translational Approach towards Precision Medicine

“…For this purpose, futibatinib has shown promising results in patients who progressed after treatment with FGFR2 inhibitors. A further partial response has recently been observed in a patient treated with futibatinib who showed disease progression after developing an acquired L618F FGFR2 kinase domain mutation following a treatment with an oral FGFR-1/2/3 inhibitor (Debio 1347) [56].…”

Pathology and molecular pathology of cholangiocarcinoma

“…the constitutive activation of FGFR2 [25] , happening between the N-terminus containing exons 1-19 of FGFR2 with a functional tyrosine kinase domain and the C-terminus that contains the partner dimerisation domain. Recently, deletion-in-frame alteration has also been described in 2.8% of cases in a large series of 178 patients, also finding that this kind of alteration is targetable with FGFR inhibitors [26] .…”