A new promising oncogenic target (p.C382R) for treatment with pemigatinib in patients with cholangiocarcinoma

Abstract

Point mutations of the fibroblast growth factor receptor (FGFR)2 receptor in intrahepatic cholangiocarcinoma (iCC) are mainly of unknown functional significance compared to FGFR2 fusions. Pemigatinib, a tyrosine kinase inhibitor, is approved for the treatment of cholangiocarcinoma with FGFR2 fusion/rearrangement. Although it is hypothesized that FGFR2 mutations may cause uncontrolled activation of the signaling pathway, the data for targeted therapies for FGFR2 mutations remain unclear. In vitro analyses demonstrated the importance of the p.C382R mutation for ligand-independent constitutive activation of FGFR2 with transforming potential. The following report describes the clinical case of a patient diagnosed with an iCC carrying a FGFR2 p.C382R point mutation which was detected in liquid, as well as in tissue-based biopsies. The patient was treated with pemigatinib, resulting in a sustained complete functional remission in fluorodeoxyglucose-positron emission tomography/computed tomography over 10 months to date. The reported case is the first description of a complete functional remission under the treatment with pemigatinib in a patient with p.C383R mutation.

Keywords: FGFR2; cholangiocarcinoma; mixed-all-nominated-in-one method; next-generation sequencing; targeted therapy; tyrosine kinase inhibitor.

Figure 1.

Structure of FGFR2: three extracellular N-terminal immunoglobulin-like extracellular domains (Ig I–III), a transmembrane alpha helix domain, and an intracellular tyrosine kinase domain. FGFR, fibroblast growth factor receptor.

Figure 2.

Regulation of FGFR2 after ligand binding and subsequent activation of intracellular pathways. The FGFR2 protein receptor consists of an extracellular domain responsible for ligand binding (FGF), a transmembrane alpha helix, and an intracellular tyrosinase domain. Ligand binding of FGF to FGFR2 results in dimerization of the two homologous protein chains of the receptor. This leads to close contact of the two intracellular alpha helix domains, followed by activation of the intracellular tyrosine kinase. The resulting autophosphorylation of FGFR2 subsequently leads to the activation of downstream signaling pathways (PI3K, RAS, and PLC-gamma) with effects on cell proliferation, cell differentiation, and cell survival. FGFR, fibroblast growth factor receptor.

Figure 3.

Ligand-independent dimerization and subsequent activation of mutant FGFR2 (p.C382R). Binding of pemigatinib leads to disruption of dimerization and thus prevents permanent activation of intracellular cell proliferation pathways. The p.C382R mutation of the FGFR2 receptor affects the transmembrane alpha helix domain of the receptor. This results in ligand-independent close contact of the transmembrane domains of both receptor chains and ligand-independent dimerization of the receptor. Herein, the activation of the intracellular tyrosine kinase domains with subsequent autophosphorylation of the receptor occurs. Binding of pemigatinib to the extracellular domains of the receptor abrogates ligand-independent receptor activation, resulting in inactivation of receptor autophosphorylation and inhibition of downstream signaling pathways. FGFR, fibroblast growth factor receptor.

Figure 4.

The histologic examination revealed a solid tumor mass with pleomorphic cells and a moderate desmoplastic stromal reaction (a: HE) and some cells with intracellular mucin deposits (b: PAS) (100 µm). Immunohistochemistry showed a focal reaction for cytokeratin 7 (c) and a strong proliferative activity for Ki67 (d) (100 µm). The staining for HER-2 was only weakly present in the tumor cells (e) and no staining could be seen for PD-L1 (f) (100 µm). HE, hematoxylin and eosin; HER-2, human epidermal growth factor receptor 2; PAS, periodic acid Schiff; PD-L1, programmed death-ligand 1.

Figure 5.

MRI scan on the left side shows the diffuse lesion expansion after the fifth cycle of first-line chemotherapy. The scan on the right side shows the response after 3 months in which the patient is in complete remission. MRI, magnetic resonance imaging.

Figure 6.

Display of complete metabolic remission 3 months after initiation of pemigatinib. Shown are MIPs (outer columns), transaxial slices of CT (inner upper column) as well as fused PET/CT (inner lower column). The patient initially presented with multiple pulmonary as well as hepatic metastases. The follow-up imaging revealed complete metabolic resolution of all lesions. CT, computed tomography; MIPs, maximum intensity projections; PET, positron emission tomography.

Figure 7.

Development of tumor markers during the clinical course and treatment. During therapy with pemigatinib, a significant decrease in the CA19-9 and CEA was observed resulting in a plateau representing complete remission. CA, carbohydrate antigen; CEA, carcinoembryonic antigen.