Selective sensitivity of EZH2 inhibitors based on synthetic lethality in ARID1A-deficient gastric cancer

Abstract

Background AT-rich interactive domain 1A (ARID1A) is a tumor suppressor gene that is 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. The histone methyltransferase EZH2 acts in a synthetic lethal manner in ARID1A-mutated ovarian cancer, although its role in GC remains unknown. Methods The selective sensitivity of the EZH2 inhibitors for ARID1A-deficient GC cells was evaluated using cell viability and colony formation assays. The expression of PI3K/AKT signaling genes were 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 phosphorylation of PI3K/AKT signaling proteins in ARID1A knock downed ARID1A-WT GC cells. 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. Bioinformatics approach revealed that the PI3K/AKT signaling was tended to be activated in ARID1A-deficient GC enhancing cell viability and, furthermore, downregulation of EZH2 in ARID1A-deficient GC was related to normalization of PI3K/AKT signaling pathway. The cell experiment revealed that phosphorylated AKT was upregulated in ARID1A-deficent GC cells. Conclusions The present findings provide a rationale for the selective sensitivity of EZH2 inhibitors against ARID1Adeficient GC and suggest the potential efficacy of targeted therapy using EZH2 inhibitors in this patient population.

Comprehensive Immunohistochemical Study of the SWI/SNF Complex Expression Status in Gastric Cancer Reveals an Adverse Prognosis of SWI/SNF Deficiency in Genomically Stable Gastric Carcinomas

“…For ARID1A-deficient cancer cells, Ogiwara et al [40] showed that they express low levels of gluthation (GSH), which makes them specifically vulnerable to inhibition of the GSH metabolic pathway. Additionally, increased sensitivity of ARID1A-deficient cancer cells to treatment with small molecule inhibitor of the PI3K/AKT pathway or selective sensitivity of EZH2 inhibitors against ARID1A-deficient gastric cancer could be demonstrated [41][42][43]. EZH2 inhibitor tazemostat is currently investigated in ongoing clinical trials including SMARCA4-negative solid tumors [18].…”

The Role of ARID1A in Tumors: Tumor Initiation or Tumor Suppression?

“…ARID1A affects the process of EMT in multiple cancers, such as gastric cancer, neuroblastoma, and liver cancer ( 37 , 96 – 98 ). In gastric cancer cell lines, the silence of ARID1A increases the expression of vimentin and N-cadherin and promotes local lymph node metastasis and distant metastasis ( 96 , 97 ). Meanwhile, knockdown of ARID1A in neuroblastoma SK-N-SH cells is found to raise the expression of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) and lessens the expression of E-cadherin, which ultimately leads to the enhancement of neuroblastoma invasion and migration ( 98 ), and the upregulated levels of MMP-9 upon ARID1A inhibition is recently shown to be due to the strengthened MMP-9 protein stability in JEG-3 choriocarcinoma cell line ( 75 ).…”

PD-L1 overexpression in EBV-positive gastric cancer is caused by unique genomic or epigenomic mechanisms

“…Immunohistochemical staining and evaluation. IHC staining of formalin-fixed, paraffin-embedded (FFPE) histological sections (4 μm thick) was performed using a polymer peroxidase method, as previously performed 19,32 . Briefly, after deparaffinization and rehydration, the sections were treated with 0.3% hydrogen peroxide in methanol for 30 min to block endogenous peroxidase activity.…”