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
4543 - Long-term real-world (RW) outcomes in patients with advanced melanoma (MEL) treated with ipilimumab (IPI) and non-IPI therapies: IMAGE study
Presenter: Stéphane Dalle
Session: Poster Display session 3
Resources:
Abstract
4523 - Prognostic Factors for efficacy of Ipilimumab used after AntiPD1 and/or BRAF+MEK inhibitors in Melanoma Patients: an Italian Melanoma Intergroup study
Presenter: Riccardo Marconcini
Session: Poster Display session 3
Resources:
Abstract
3632 - Rechallenge with combination ipilimumab and anti-PD-1 (IPI+PD1) in metastatic melanoma after acquired resistance to IPI+PD1 immunotherapy
Presenter: Adriana Hepner
Session: Poster Display session 3
Resources:
Abstract
3732 - Clinicopathologic characteristics of immune colitis in melanoma patients treated with combination ipilimumab and anti-PD1 (IPI+PD1) and PD1 monotherapy.
Presenter: Kazi Nahar
Session: Poster Display session 3
Resources:
Abstract
5005 - Real-world outcomes of ipilimumab plus nivolumab for advanced melanoma in the Netherlands
Presenter: Michiel van Zeijl
Session: Poster Display session 3
Resources:
Abstract
5524 - Utilization of Real-World Data to Assess the Effectiveness of Immune Checkpoint Inhibitors (ICIs) in Elderly Patients with Metastatic Melanoma
Presenter: D Scott Ernst
Session: Poster Display session 3
Resources:
Abstract
5884 - Tumor mutational burden and response to PD-1 inhibitors: an analysis of 89 cases of metastatic melanoma.
Presenter: Léa Dousset
Session: Poster Display session 3
Resources:
Abstract
3120 - Increase in S100B and LDH as early outcome predictors for non-responsiveness to anti-PD-1 monotherapy in advanced melanoma.
Presenter: Elisa Rozeman
Session: Poster Display session 3
Resources:
Abstract
2157 - Immune status defined by molecular information layers predicts response to pembrolizumab treatment in advanced melanoma
Presenter: Guillermo Prado-Vázquez
Session: Poster Display session 3
Resources:
Abstract
2553 - Interim analysis of a phase Ib study of cobimetinib plus atezolizumab in patients with advanced BRAFV600 wild type melanoma progressing on prior anti-PD-L1 therapy
Presenter: Shahneen Sandhu
Session: Poster Display session 3
Resources:
Abstract