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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.

SUBMITTER: Hempel L

PROVIDER: S-EPMC9520138 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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

Hempel Louisa L Lapa Constantin C Dierks Alexander A Gaumann Andreas A Scheiber Josef J Veloso de Oliveira Julia J Philipp Patrick P Oyarzun Laura Cristina C Wesarg Stefan S Robert Sebastian S Hempel Dirk D

Therapeutic advances in medical oncology 20220926

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. <i>In vi ...[more]

PMID: 36188486

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Project description:Cholangiocarcinoma (CCA) is a primary malignant tumor of the liver, typically diagnosed in advanced stages. Surgical resection remains the principal treatment method in clinical practice. Regrettably, the majority of patients receive their diagnosis at an advanced stage, making surgical intervention unfeasible. While chemotherapy serves as the main palliative treatment for advanced CCA, its effectiveness is significantly limited due to the rapid development of chemoresistance. Studying the pathogenesis of CCA and new resistance targets is crucial for improving clinical outcomes. In our current study, we first identified the expression of SLC16A1 in the transcriptome and proteome of human tumors and found abnormal expression of SLC16A1 in various human cancers. Subsequently, we focused our attention on the role of SLC16A1 in CCA. Utilizing bioinformatics analysis, we pioneered the identification of the clinical significance of SLC16A1 in this type of cancer. Specifically, higher expression levels of SLC16A1 were observed in CCA patients with venous invasion and higher T and M stages. Additionally, patients with higher SLC16A1 expression had poorer prognoses. These results suggest the oncogenic role of SLC16A1 in CCA. Further immune infiltration analysis revealed a significant correlation between SLC16A1 and the infiltration levels of cells like neutrophils and macrophages in the tumor microenvironment, indicating SLC16A1's potential involvement in regulating the tumor immune microenvironment of CCA. Moreover, results from functional and pathway enrichment analyses revealed that SLC16A1 might affect clinical outcomes in CCA patients by participating in drug metabolism processes. Finally, through further in vitro and in vivo experiments, we confirmed that SLC16A1, as an oncogene in CCA, promotes the growth of CCA cells and chemoresistance. Knocking down SLC16A1 inhibited the growth of CCA cells and enhanced their sensitivity to 5-Fluorouracil (5-FU). Overall, this study reveals the key role of SLC16A1 in the development of CCA and highlights its significance as a potential target for improving treatment efficacy and chemotherapy sensitivity.

Project description:BackgroundFibroblast growth factor receptor 2 (FGFR2) fusions and rearrangements are clinically actionable genomic alterations in cholangiocarcinoma (CCA). Pemigatinib is a selective, potent, oral inhibitor of FGFR1-3 and demonstrated efficacy in patients with previously treated, advanced/metastatic CCA with FGFR2 alterations in FIGHT-202 (NCT02924376). We report final outcomes from the extended follow-up period.Patients and methodsThe multicenter, open-label, single-arm, phase II FIGHT-202 study enrolled patients ≥18 years old with previously treated advanced/metastatic CCA with FGFR2 fusions or rearrangements (cohort A), other FGF/FGFR alterations (cohort B), or no FGF/FGFR alterations (cohort C). Patients received once-daily oral pemigatinib 13.5 mg in 21-day cycles (2 weeks on, 1 week off) until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) in cohort A assessed as per RECIST v1.1 by an independent review committee; secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.ResultsFIGHT-202 enrolled 147 patients (cohort A, 108; cohort B, 20; cohort C, 17; unconfirmed FGF/FGFR alterations, 2). By final analysis, 145 (98.6%) had discontinued treatment due to progressive disease (71.4%), withdrawal by patient (8.2%), or adverse events (AEs; 6.8%). Median follow-up was 45.4 months. The ORR in cohort A was 37.0% (95% confidence interval 27.9% to 46.9%); complete and partial responses were observed in 3 and 37 patients, respectively. Median DOR was 9.1 (6.0-14.5) months; median PFS and OS were 7.0 (6.1-10.5) months and 17.5 (14.4-22.9) months, respectively. The most common treatment-emergent AEs (TEAEs) were hyperphosphatemia (58.5%), alopecia (49.7%), and diarrhea (47.6%). Overall, 15 (10.2%) patients experienced TEAEs leading to pemigatinib discontinuation; intestinal obstruction and acute kidney injury (n = 2 each) occurred most frequently.ConclusionsPemigatinib demonstrated durable response and prolonged OS with manageable AEs in patients with previously treated, advanced/metastatic CCA with FGFR2 alterations in the extended follow-up period of FIGHT-202.

Project description:BackgroundIntegration of HBV DNA into the human genome could progressively contribute to hepatocarcinogenesis. Both intrahepatic cholangiocarcinoma (ICC) and combined hepatocellular-cholangiocarcinoma (CHC) are known to be associated with HBV infection. However, the integration of HBV and mechanism of HBV-induced carcinogenesis in ICC and CHC remains unclear.Methods41 patients with ICC and 20 patients with CHC were recruited in the study. We conducted HIVID analysis on these 61 samples to identify HBV integration sites in both the tumor tissues and adjacent non-tumor liver tissues. To further explore the effect of HBV integration on gene alteration, we selected paired tumors and adjacent non-tumor liver tissues from 3 ICC and 4 CHC patients for RNA-seq and WGS.ResultsWe detected 493 HBV integration sites in ICC patients, of which 417 were from tumor samples and 76 were from non-tumor samples. And 246 HBV integration sites were detected in CHC patients, of which 156 were located in the genome of tumor samples and 90 were in non-tumor samples. Recurrent HBV integration events were detected in ICC including TERT, ZMAT4, MET, ANKFN1, PLXNB2, and in CHC like TERT, ALKBH5. Together with our established data of HBV-infected hepatocellular carcinoma, we found that HBV preferentially integrates into the specific regions which may affect the gene expression and regulation in cells and involved in carcinogenesis. We further performed genomic and transcriptomic sequencing of three ICC and four CHC patients, and found that HBV fragments could integrate near some important oncogene like TERT, causing large-scale genome variations on nearby genomic sequences, and at the same time changing the expression level of the oncogenes.ConclusionComparative analysis demonstrates numerous newly discovered mutational events in ICC and CHC resulting from HBV insertions in the host genome. Our study provides an in-depth biological and clinical insights into HBV-induced ICC and CHC.

Dataset Information

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

Publications

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

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