Abstract 1462
Background
Esophageal squamous cell carcinoma (ESCC) with high mortality is particularly prevalent in China and the prognosis is poor. Although genetic amplification and overexpression of the fibroblast growth factor 19 (FGF19) gene are found in ESCC, mechanisms that contribute to such functional alterations remain elusive.
Methods
Gene-Panel Sequencing was used to detect genetic variants that may be associated with a risk of ESCC. The effect of proliferation inhibition of LY2874455, which is inhibitor of fibroblast growth factor receptors (FGFR), was assessed in ESCC patient-derived cell (PDC) and xenograft (PDX) models. Autophagic activity was evaluated by immunoblotting for microtubule-associated protein 1 light chain 3 (LC3) and p62.
Results
Using Gene-Panel Sequencing of 161 FFPE tissues, we found that FGF19 copy number amplified in almost 30% ESCC. Pharmacological of FGF19/FGFR by LY2874455 significantly induces repression of FGF19 amplificated ESCC progression in either PDC or PDX models. Mechanistic study revealed that treatment with LY2874455 induced activity of autophagy by inhibiting the ERK/MAPK pathway not by AKT pathway.
Conclusions
Our findings reveal that FGF19 amplification inhibits autophagic activity by increasing the phosphorylation level of ERK, which may play an essential role in the pathogenesis of ESCC. Using FGFR inhibitor may represent an effective strategy to suppress FGF19 amplificated ESCC development and progression.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
The Major Project of Health Commission of Zhejiang Province of China (No. WKJ-ZJ-1902), the Public Welfare Technology Foundation of Zhejiang Province of China (No. 2017C34001), Zhejiang high-level innovative talent program, and the 1022 program of Zhejiang Cancer Hospital.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
3140 - Phase 2 study of olaparib in previously treated advanced solid tumors with homologous recombination repair mutation (HRRm) or homologous recombination repair deficiency (HRD): LYNK-002
Presenter: David Hyman
Session: Poster Display session 3
Resources:
Abstract
2655 - The K-BASKET trial: A prospective phase II biomarker-driven multiple basket trial in Korean solid cancer patients.
Presenter: Seul Kim
Session: Poster Display session 3
Resources:
Abstract
5938 - Cambridge Liquid biopsy “CALIBRATION” study: Can changes in circulating tumour DNA (ctDNA) predict durable tumour responses in patients with advanced oesophageal cancer receiving MEDI4736?
Presenter: Constanza Linossi
Session: Poster Display session 3
Resources:
Abstract
3799 - Validation of a tumour mutational burden workflow on routine histological samples of colorectal cancer and assessment of a cohort with synchronous hepatic metastases
Presenter: Andrea Mafficini
Session: Poster Display session 3
Resources:
Abstract
4647 - Microsatellite Instability Testing and Lynch Syndrome Screening For Colorectal Cancer Patients Through Tumor Sequencing
Presenter: Li Liu
Session: Poster Display session 3
Resources:
Abstract
3231 - "Liquid Withdarw" technique in CT-guided cutting needle lung biopsy: decreased incidence of complications and increased tissue amount for lung cancer molecular testing.
Presenter: Xue Wang
Session: Poster Display session 3
Resources:
Abstract
3282 - WGS Implementation in standard cancer Diagnostics for Every cancer patient (WIDE)
Presenter: Paul Roepman
Session: Poster Display session 3
Resources:
Abstract
5905 - Known and unknown gene fusion detection capabilities of solid tumor laboratories conducting next generation sequencing in 6 countries
Presenter: Steph Finucane
Session: Poster Display session 3
Resources:
Abstract
4238 - Clinical and Analytical Accuracy of a 523 Gene Panel Next-Generation Sequencing (NGS) Assay on Formalin-Fixed Paraffin-Embedded (FFPE) Solid Tumor Samples
Presenter: Ina Deras
Session: Poster Display session 3
Resources:
Abstract
2493 - Methylation analysis of MLH1 using droplet digital PCR and methylation sensitive restriction enzyme.
Presenter: Celine De Rop
Session: Poster Display session 3
Resources:
Abstract