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Advances in Radiotherapy
& Nuclear Medicine EZH2 inhibition in ARID1A-deficient TNBC

Table 1. Key clinical studies of immunotherapy in AT-rich interactive domain 1A-deficient tumors
Reference Tumor type Study design Key findings
Chen et al. 13 TNBC Cohort study Kaplan–Meier PFS analysis based on ARID1A and
PD-L1 expression demonstrated that patients with low
ARID1A expression had a significantly longer PFS
Duran et al. 117 Metastatic lung adenocarcinoma with ARID1A Case report 19-month partial response maintained with
mutations nivolumab
Goswami et al. 118 Metastatic urothelial carcinoma Cohort study ARID1A mutation and CXCL13 expression as
combinatorial biomarkers in baseline tumor tissues
suggested improved OS compared to either single
biomarker from immunotherapy
Li et al. 119 Gastrointestinal cancer Cohort study Improved OS with immunotherapy in ARID1A-
mutated cancers versus ARID1A-wildtype cancers
Pignata et al. 120 Advanced endometrial cancer Pre-planned transitional Improved treatment effect with avelumab with
analysis of the MITO END-3 ARID1A mutation
randomized trial
Sun et al. 8 NSCLC Cohort study More responders (CR+PR+SD) with ARID1A
mutation (50 vs. 19%, P=0.045); trend for median
survival with ARID1A mutation
(6.8 vs. 5.5 months, P=0.313)
Sun et al. 10 Gastric cancer Cohort study ARID1A-deficiency associated with improved OS
with immunotherapy (HR: 0.39; 95%
CI: 0.15 – 0.98, P=0.044)
Zhou et al. 121 Solid tumors (gastric, endometrial, NSCLC, Retrospective study ARID1A mutations (majority inactivating)
cholangiocarcinoma, esophageal, urothelial, associated with longer median overall survival after
ovarian, colon, breast, and pancreatic cancer) immunotherapy (51 vs. 41 months)
Abbreviations: ARID1A: AT-rich interactive domain 1A; CI: Confidence interval; CR: Complete response; HR: Hazard ratio; NSCLC: Non-small cell
lung carcinoma; OS: Overall survival; PD-L1: Programmed cell death ligand 1; PFS: Progression-free survival; PR: Partial response; SD: Stable disease;
TNBC: Triple-negative breast cancer.

including mutations antagonizing the SWI/SNF chromatin strongly associated with the TNBC phenotype. 22,23 In
remodeling complex. This contribution raises the breast cancer, EZH2 overexpression promotes initiation,
20
possibility of synthetic lethality, as both ARID1A and invasion, and metastasis. Studies using human breast
24
EZH2 can silence the PI3K-interacting protein 1 gene tissue samples have shown that EZH2 expression is low
(PIK3IP1) and subsequently promote cell proliferation in normal epithelium but increases with the degree of
24
and anti-apoptotic effects through PI3K/AKT signaling. atypia. EZH2 levels increase progressively from atypical
20
Low ARID1A expression leads to unbalanced EZH2 ductal hyperplasia to ductal carcinoma in situ and invasive
activity, which is hypothesized to drive tumorigenesis. carcinomas, with the highest expression observed in
20
25
Inhibition of EZH2 has been shown to upregulate PIK3IP1 distant metastases. High levels of EZH2 in primary
expression in ARID1A-deficient ovarian cancer cells, breast carcinomas are significantly linked to estrogen
thereby suppressing cell growth by inhibiting PI3K/AKT receptor-negative status, which is indicative of poor tumor
signaling as depicted in Figure 1. 21 differentiation and acts as an independent biomarker for
patient survival. 24
2. Enhancer of zeste homolog 2 in TNBC
The canonical mechanism by which EZH2 contributes
Epigenetic modulations in TNBC encompass several to cancer development and progression is primarily
key processes: DNA methylation (inactivation of gene attributed to H3K27me3-mediated transcriptional
transcription), hypomethylation (gene activation), silencing; however, non-canonical functions of EZH2 have
histone acetylation (transcriptional activation), and also been reported. Imbalances in methyltransferases,
24
histone methylation (transcriptional inhibition). Histone such as EZH2, can lead to histone methylation
16
methylation is modulated by methyltransferases, such as dysregulation, which subsequently alters chromatin
EZH2. High expression of EZH2 has been found across structure and gene expression. Enhanced EZH2 activity
16
various cancer types, including breast, prostate, bladder, has been associated with tumor cell proliferation and
colon, lung, pancreas, sarcoma, and lymphoma, and is metastasis in various subtypes of breast cancer through the

Volume 3 Issue 1 (2025) 30 doi: 10.36922/arnm.5132