ARID1A, ARID1B, and ARID2 Mutations Serve as Potential Biomarkers for Immune Checkpoint Blockade in Patients With Non-Small Cell Lung Cancer

Abstract

Worldwide, non-small cell lung cancer (NSCLC) has the highest morbidity and mortality of all malignancies. The lack of responsiveness to checkpoint inhibitors is a central problem in the modern era of cancer immunotherapy, with the rapid development of immune checkpoint inhibitors (ICIs) in recent years. The human switch/sucrose nonfermentable (SWI/SNF) chromatin-remodeling complex has been reported to be recurrently mutated in patients with cancer, and those with SWI/SNF mutations have been reported to be sensitive to ICIs. Six reported cohorts, a total of 3416 patients, were used to analyze the mutation status of ARID1A, ARID1B, ARID2 and SMARCA4 in patients with NSCLC and the effect of mutations on prognosis after ICIs. Finally, a nomogram was established to guide the clinical use of ICIs. The results show that patients with NSCLC who have ARID1A, ARID1B, and ARID2 mutations of the SWI/SNF complex were more likely to benefit from ICI therapy.

Correlations of switch/sucrose nonfermentable complex mutations with clinical outcomes in advanced non–small cell lung cancer

“…In our institutional study of 1162 Chinese patients with NSCLC, we reported a mutational incidence rate of 20% in SWI/SNF genes. Consistent with previous studies, 9,11,19,20 SWI/SNF-mut was correlated with older age, smoking, male sex, higher TMB, and higher proportion of PD-L1-positive. Moreover, SWI/SNF-mut was more often observed in tumors with advanced disease, bone, and liver metastasis.…”

“…7,8 In NSCLC, ARID1A, and SMARCA4 were the most frequently mutated genes, which occur in 8% to 9% of patients. [8][9][10][11] The impact of SWI/SNF gene mutations on the efficacy of immune checkpoint inhibitors (ICIs) in NSCLC has recently drawn considerable attention. A retrospective study among 292 NSCLC patients treated with ICIs found that patients with SMARCA4 alterations had improved overall survival (OS) (hazard ratio [HR], 0.67; p = 0.01).…”

“…In NSCLC, ARID1A, and SMARCA4 were the most frequently mutated genes, which occur in 8% to 9% of patients 8–11 . The impact of SWI/SNF gene mutations on the efficacy of immune checkpoint inhibitors (ICIs) in NSCLC has recently drawn considerable attention.…”

Targeting Chromatin-Remodeling Factors in Cancer Cells: Promising Molecules in Cancer Therapy

“…Recent evidence has suggested that the epigenetic alterations caused by chromatin mediators, such as chromatin remodelers, cooperatively drive tumor progression and immunotherapy resistance [ 159 ]. For instance, the mutations in several of the chromatin remodeler encoding genes, such as ARID1A, ARID1B, and ARID2, have been confirmed to be more likely to benefit from immune checkpoint blockade therapy for NSCLC patients [ 160 , 161 ]. Another recent study has further delineated the tumor-promoting role of the SWI/SNF component SMARCC1 in HCC.…”

“…Knowledge of chromatin remodeling in the regulation of immunotherapies, especially the immune checkpoint inhibitors (ICIs) in cancer, has yielded several promising therapeutic strategies that show great benefits to patients. Genetic alterations in ARID family members have been revealed to be related to sensitivity to ICI therapy in cancer [ 211 ], such as in NSCLC [ 160 ], EBV-positive gastric cancers [ 212 ], and ovarian cancer ( Figure 4 ) [ 213 , 214 ]. For example, ARID1A alters sensitize tumors to immune checkpoint blockade, suggesting a potential candidate for immunotherapy [ 215 ].…”