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

Chang, Geyun; Li, Weihua; Bai, Hua; Duan, Jianchun; Wang, Zhijie; Du, Xinyang; Yu, Ruofei; Wang, Yaxi; Wang, Minghao; Zhu, Yixiang; Zhang, Xue; Li, Li; Wan, Rui; Wang, Jie

doi:10.1111/1759-7714.14635

Cited by 3 publications

(2 citation statements)

References 42 publications

(87 reference statements)

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“…Results from a few studies suggested that NSCLC patients with a deficiency of SWI or SNF might be more sensitive to ICI treatment [ 109 , 110 , 112 , 113 , 114 , 115 , 117 ].…”

Section: Outcome Of Ici Treatment For Nsclc With Deficiency Of Swi/snfmentioning

confidence: 99%

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Dysregulation of SWI/SNF Chromatin Remodelers in NSCLC: Its Influence on Cancer Therapies including Immunotherapy

Shi

Shin

2023

Biomolecules

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Lung cancer is the leading cause of cancer death worldwide. Molecularly targeted therapeutics and immunotherapy revolutionized the clinical care of NSCLC patients. However, not all NSCLC patients harbor molecular targets (e.g., mutated EGFR), and only a subset benefits from immunotherapy. Moreover, we are lacking reliable biomarkers for immunotherapy, although PD-L1 expression has been mainly used for guiding front-line therapeutic options. Alterations of the SWI/SNF chromatin remodeler occur commonly in patients with NSCLC. This subset of NSCLC tumors tends to be undifferentiated and presents high heterogeneity in histology, and it shows a dismal prognosis because of poor response to the current standard therapies. Catalytic subunits SMARCA4/A2 and DNA binding subunits ARID1A/ARID1B/ARID2 as well as PBRM1 were identified to be the most commonly mutated subunits of SWI/SNF complexes in NSCLC. Mechanistically, alteration of these SWI/SNF subunits contributes to the tumorigenesis of NSCLC through compromising the function of critical tumor suppressor genes, enhancing oncogenic activity as well as impaired DNA repair capacity related to genomic instability. Several vulnerabilities of NSCLCS with altered SWI/SNF subunits were detected and evaluated clinically using EZH2 inhibitors, PROTACs of mutual synthetic lethal paralogs of the SWI/SNF subunits as well as PARP inhibitors. The response of NSCLC tumors with an alteration of SWI/SNF to ICIs might be confounded by the coexistence of mutations in genes capable of influencing patients’ response to ICIs. High heterogenicity in the tumor with SWI/SNF deficiency might also be responsible for the seemingly conflicting results of ICI treatment of NSCLC patients with alterations of SWI/SNF. In addition, an alteration of each different SWI/SNF subunit might have a unique impact on the response of NSCLC with deficient SWI/SNF subunits. Prospective studies are required to evaluate how the alterations of the SWI/SNF in the subset of NSCLC patients impact the response to ICI treatment. Finally, it is worthwhile to point out that combining inhibitors of other chromatin modulators with ICIs has been proven to be effective for the treatment of NSCLC with deficient SWI/SNF chromatin remodelers.

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“…Results from a few studies suggested that NSCLC patients with a deficiency of SWI or SNF might be more sensitive to ICI treatment [ 109 , 110 , 112 , 113 , 114 , 115 , 117 ].…”

Section: Outcome Of Ici Treatment For Nsclc With Deficiency Of Swi/snfmentioning

confidence: 99%

“…It is noteworthy that all the listed studies were retrospective except for one case report. Results from a few studies suggested that NSCLC patients with a deficiency of SWI or SNF might be more sensitive to ICI treatment [109,110,[112][113][114][115]117].…”

Section: Outcome Of Ici Treatment For Nsclc With Deficiency Of Swi/snfmentioning

confidence: 99%

Dysregulation of SWI/SNF Chromatin Remodelers in NSCLC: Its Influence on Cancer Therapies including Immunotherapy

Shi

Shin

2023

Biomolecules

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

Chang

Bai

et al. 2022

Thoracic Cancer

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Background: The switch/sucrose nonfermentable complex mutations (SWI/SNF-mut) are common in non-small cell lung cancer (NSCLC). However, the association of SWI/SNF-mut with the clinical outcomes of immune checkpoint inhibitors (ICIs), particularly of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), has not been established. Methods: We retrospectively collected data of patients at Cancer Hospital Chinese Academy of Medical Sciences. Patients with advanced NSCLC who received programmed cell death protein-1 or programmed cell death ligand 1 (PD-[L]1) inhibitors were included in cohort 1 and those with EGFR mutations (EGFR-mutant) received EGFR-TKIs monotherapy were included in cohort 2. Two reported Memorial Sloan-Kettering Cancer Center (MSKCC) cohorts received immunotherapy alone used as the validation for cohort 1. We analyzed the relationship between SWI/SNF alterations and clinical outcomes in each cohort. Results: In total, 1162 patients were included, of which 230 patients (19.8%) were identified as SWI/SNF-mut with the most common genetic alterations being ARID1A (33.4%) and SMARCA4 (28.3%). In cohort 1 (n = 146), patients with co-mutations of SWI/SNF and Kirsten rat sarcoma oncogene (KRAS) (SWI/SNFmutKRASmut, n = 18) had significantly prolonged progression-free survival (PFS) (8.6 m vs. 1.9 m; hazard ratio [HR], 0.31; 95% confidence intervals [CI], 0.11-0.83; p = 0.032) to PD-(L)1 inhibitors monotherapy, which was consistent with the MSKCC cohorts (not reach [NR] vs. 6.3 m; HR, 0.36, 95% CI, 0.15-0.82; p = 0.016). In cohort 2 (n = 205), ARID1A-mut (n = 16) was associated with improved PFS after EGFR-TKIs (20.6 m vs. 11.2 m; HR, 0.47, 95% CI, 0.27-0.94; p = 0.023). Conclusions: In advanced NSCLC, patients with SWI/SNFmutKRASmut seem to benefit more from ICIs. Furthermore, ARID1A-mut may provide a protective effect to EGFR-TKIs in EGFR-mutant patients. However, this is a retrospective singleinstitution analysis that requires further validation by large prospective studies.K E Y W O R D S epidermal growth factor receptor, immune checkpoint inhibitors, non-small cell lung cancer, SWI/SNF, tyrosine kinase inhibitors

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A Critical Review of the Impact of SMARCA4 Mutations on Survival Outcomes in Non-Small Cell Lung Cancer

Manolakos,

Boccuto,

Ivankovic

2024

JPM

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This critical review investigates the impact of SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4) mutations on survival outcomes in non-small cell lung cancer (NSCLC) through an analysis of 21 peer-reviewed articles. Survival analyses across this review demonstrated consistently worse outcomes for SMARCA4-mutated vs. SMARCA4 wild-type NSCLC patients, specifically emphasizing class 1 truncating mutations as an independent factor for poor overall survival. In addition, this review explores the clinicopathologic characteristics of SMARCA4 mutations and their impact on various treatment modalities, including immune checkpoint inhibitors (ICIs) both with and without Kirsten rat sarcoma viral oncogene homolog (KRAS) co-mutations. The potential ineffectiveness of ICI treatment in NSCLC is explored through the impact of SMARCA4/KRAS co-mutations on the tumor microenvironment. Moreover, this NSCLC review consistently reported statistically worse overall survival outcomes for SMARCA4/KRAS co-mutations than SMARCA4 wild-type/KRAS-mutated cohorts, extending across ICIs, chemo-immunotherapy (CIT), and KRAS G12C inhibitors. Designing prospective clinical SMARCA4-mutated or SMARCA4/KRAS co-mutated NSCLC trials to evaluate targeted therapies and immunotherapy may lead to a better understanding of how to improve cancer patients’ outcomes and survival rates.

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

Cited by 3 publications

References 42 publications

Dysregulation of SWI/SNF Chromatin Remodelers in NSCLC: Its Influence on Cancer Therapies including Immunotherapy

Dysregulation of SWI/SNF Chromatin Remodelers in NSCLC: Its Influence on Cancer Therapies including Immunotherapy

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

A Critical Review of the Impact of SMARCA4 Mutations on Survival Outcomes in Non-Small Cell Lung Cancer

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