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.
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