Abstract 75P
Background
AT-rich interactive domain 1A (ARID1A) is a tumor suppressor gene and frequently mutated in gastric cancer (GC). Although ARID1A mutations are not a druggable target for conventional treatments, novel therapeutic strategies based on a synthetic lethal approach are effective for ARID1A-deficient cancers. EZH2, the histone methyltransferase and a member of the polycomb repressive complex 2 (PRC2), catalyzes the trimethylation of lysine 27 on histone 3 and showed a synthetic lethality in ARID1A-mutated ovarian cancer, but its role in GC has not been investigated yet.
Methods
The selective sensitivity of the EZH2 inhibitors for ARID1A-deficient GC cells was evaluated using cell viability and colony formation assays enrolling three kinds of EZH2 inhibitors. The expression of PI3K/AKT signaling genes was investigated using TCGA’s cBioPortal database to determine whether the homeostasis between ARID1A and EZH2 is related to cell proliferation and survival via the PI3K/AKT signaling pathway. We also evaluated the expression of EZH2, PD-L1, and PD-L2, MSI status, and EBV infection were investigated in ARID1A negative GC using patient samples.
Results
EZH2 inhibitors decreased the viability of ARID1A-deficient cells in a dose-dependent manner and demonstrated the selective sensitivity to ARID1A-deficient cells in vitro experiment system. A bioinformatics approach revealed that the PI3K/AKT signaling tended to be activated in ARID1A-deficient GC enhancing cell viability and, furthermore, down-regulation of EZH2 in ARID1A-deficient GC was related to normalization of PI3K/AKT signaling pathway. Clinicopathological characteristics of ARID1A negative GC with ARID1A, EZH2, PD-L1, and PD-L2 expressions, MSI, and EBV status were summarized.
Conclusions
The present findings provide a rationale for the selective sensitivity of EZH2 inhibitors against ARID1A-deficient GC and suggest the potential efficacy of targeted therapy using EZH2 inhibitors in this patient population.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
144P - Clinical implication of DNA damage response gene in patients with stage II or III gastric cancer
Presenter: In Gyu Hwang
Session: e-Poster Display Session
145P - A nomogram for predicting the benefit of adjuvant chemotherapy after resection in patients with Borrmann type IV gastric cancer
Presenter: Qing-Zhu Qiu
Session: e-Poster Display Session
146P - Red cell distribution width and mean corpuscular volume ratio as a promising new marker for chemotherapy effects in remnant gastric cancer: An analysis of a multi-institutional database
Presenter: Kai-Xiang Xu
Session: e-Poster Display Session
147P - Can the clinical stage of the 8th edition of the Union for International Cancer Control TNM classification stratify prognosis of patients with Siewert type II/III cancer?
Presenter: Hayato Watanabe
Session: e-Poster Display Session
148P - MCV-the ideal answer to predict the prognosis of remnant gastric cancer: An analysis from a multi-institutional database
Presenter: Kai Weng
Session: e-Poster Display Session
149P - Molecular and clinical characteristics of patients with resectable gastric cancer
Presenter: Zhi Zheng
Session: e-Poster Display Session
150P - Real-world assessment of the treatment patterns associated with unresectable advanced and metastatic gastric cancer in China
Presenter: Xiao Sun
Session: e-Poster Display Session
151P - Treatment patterns, healthcare resource use, economic and survival outcomes associated with unresectable advanced metastatic gastric cancers in Taiwan
Presenter: Chee Jen Chang
Session: e-Poster Display Session
152P - ARID1A deficiency in EBV-positive gastric cancer is partially regulated by EBV-encoded miRNAs, but not by DNA promotor hypermethylation
Presenter: Koji Kase
Session: e-Poster Display Session
153P - Mutational landscape of gastric cancer (GC) in adolescents and young adults (AYA) in Asia from 2015-2019
Presenter: Evelyn Yi Ting Wong
Session: e-Poster Display Session