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Background <p>Switch/sucrose nonfermentable (SWI/SNF) complex mutations have been reported in Kirsten rat sarcoma viral oncogene homologue (<i>KRAS</i>)-mutant non-small cell lung cancer (NSCLC), but the influence on immune checkpoint blockade (ICB) outcomes is debated and needs to be investigated further.</p> Methods <p>Genomic pathogenic alterations (GPAs) in SWI/SNF genes were identified via OncoKB, COSMIC and PolyPhen-2. NSCLC patients (NSCLCs) were classified according to alterations in six SWI/SNF genes (<i>ARID1A</i>, <i>ARID1B</i>, <i>ARID2</i>, <i>PBRM1</i>, <i>SMARCA4</i> and <i>SMARCB1</i>). Cell lines used for differentially expressed gene analyses were subjected to RNA sequencing (RNA-seq) and Western blotting to validate protein expression levels. Protein expression in tumour specimens was detected by immunohistochemistry (IHC).</p> Results <p>In 2660 NSCLCs, 15.0% (401/2660) had SWI/SNF GPAs. A total of 23.1% (69/299) of the <i>EGFR</i><sup><i>wt</i></sup><i>ALK</i><sup><i>wt</i></sup> NSCLCs and 27.8% (25/90) of the <i>STK11</i><sup><i>wt</i></sup><i>KEAP1</i><sup><i>wt</i></sup><i>KRAS</i><sup><i>mut</i></sup> NSCLCs who received ICB had SWI/SNF GPAs. Among all the ICB-treated NSCLCs, progression-free survival (PFS) was not significantly different between SWI/SNF-wild type (wt) and SWI/SNF-mutant (mut) NSCLCs. However, GPAs in the SWI/SNF complex in <i>KRAS</i>-mut ICB-treated NSCLCs were associated with poorer clinical outcomes. Patients with <i>ARID1A</i>/<i>ARID1B</i>/<i>ARID2</i>/<i>PBRM1</i> mutations had a significantly shorter PFS (2.7 vs. 6.5&#xa0;m, HR = 2.44 [95% CI 1.31–4.54], <i>P</i> = 0.004) than did those with SWI/SNF-wt. Among <i>STK11</i><sup><i>wt</i></sup><i>KEAP1</i><sup><i>wt</i></sup><i>KRAS</i><sup><i>mut</i></sup> NSCLCs, all SWI/SNF-mut (4.9 vs. 9.1&#xa0;m, HR = 2.03 [95% CI 1.07–3.86], <i>P</i> = 0.029) and <i>ARID1A/ARID1B/ARID2/PBRM1</i>-mut (3.2 vs. 9.1&#xa0;m, HR = 2.68 [95% CI 1.33–5.41], <i>P</i> = 0.004) NSCLCs had significantly shortened PFS, and <i>ARID1A/ARID1B/ARID2</i>-mut NSCLCs also tended to have a shorter overall survival (OS) (12.2 vs. 29.9&#xa0;m, HR = 2.20 [95% CI 0.98–4.91], <i>P</i> = 0.052). Furthermore, RNA-seq and Western blot analyses confirmed that the deletion of SWI/SNF genes resulted in downregulated STING expression in NSCLC cell lines. And IHC analysis of patient tumour samples confirmed that the loss of SWI/SNF protein expression was associated with decreased STING protein levels. Notably, downregulated STING protein expression was observed in <i>KRAS</i>-mut NSCLC patients who did not benefit from ICB treatment.</p> Conclusions <p>In <i>KRAS</i>-mut NSCLCs with or without <i>STK11/KEAP1</i> mutations, the GPAs in the DNA-binding genes <i>ARID1A</i>/<i>ARID2</i> affected the outcomes of immunotherapy, possibly through the downregulation of STING expression.</p>

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Genomic pathogenic alterations in the SWI/SNF complex compromise the outcomes of immunotherapy in Chinese patients with KRAS-mutant NSCLC by downregulating STING expression

  • 期刊论文

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  • 发表日期：

    2025年12月3日

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  • Lingling Gao,
  • Jie Jiang,
  • Linlin Zhu,
  • Zhi Xie,
  • Yu Chen,
  • Zhiyi Lv,
  • Yuqing Chen,
  • Wenbin Zhou,
  • Ji Chen,
  • Yumin Zhong,
  • Li Zhang,
  • Penghui Zeng,
  • Xiaodan Huang,
  • Wenqing Yan,
  • Danxia Lu,
  • Shuilian Zhang,
  • Weibang Guo,
  • Dongkun Zhang,
  • Haiyu Zhou,
  • Weineng Feng,
  • Binchao Wang,
  • Zunfu Ke,
  • Xuening Yang,
  • Hongling Liang,
  • Xuchao Zhang

摘要

Background

Switch/sucrose nonfermentable (SWI/SNF) complex mutations have been reported in Kirsten rat sarcoma viral oncogene homologue (KRAS)-mutant non-small cell lung cancer (NSCLC), but the influence on immune checkpoint blockade (ICB) outcomes is debated and needs to be investigated further.

Methods

Genomic pathogenic alterations (GPAs) in SWI/SNF genes were identified via OncoKB, COSMIC and PolyPhen-2. NSCLC patients (NSCLCs) were classified according to alterations in six SWI/SNF genes (ARID1A, ARID1B, ARID2, PBRM1, SMARCA4 and SMARCB1). Cell lines used for differentially expressed gene analyses were subjected to RNA sequencing (RNA-seq) and Western blotting to validate protein expression levels. Protein expression in tumour specimens was detected by immunohistochemistry (IHC).

Results

In 2660 NSCLCs, 15.0% (401/2660) had SWI/SNF GPAs. A total of 23.1% (69/299) of the EGFRwtALKwt NSCLCs and 27.8% (25/90) of the STK11wtKEAP1wtKRASmut NSCLCs who received ICB had SWI/SNF GPAs. Among all the ICB-treated NSCLCs, progression-free survival (PFS) was not significantly different between SWI/SNF-wild type (wt) and SWI/SNF-mutant (mut) NSCLCs. However, GPAs in the SWI/SNF complex in KRAS-mut ICB-treated NSCLCs were associated with poorer clinical outcomes. Patients with ARID1A/ARID1B/ARID2/PBRM1 mutations had a significantly shorter PFS (2.7 vs. 6.5 m, HR = 2.44 [95% CI 1.31–4.54], P = 0.004) than did those with SWI/SNF-wt. Among STK11wtKEAP1wtKRASmut NSCLCs, all SWI/SNF-mut (4.9 vs. 9.1 m, HR = 2.03 [95% CI 1.07–3.86], P = 0.029) and ARID1A/ARID1B/ARID2/PBRM1-mut (3.2 vs. 9.1 m, HR = 2.68 [95% CI 1.33–5.41], P = 0.004) NSCLCs had significantly shortened PFS, and ARID1A/ARID1B/ARID2-mut NSCLCs also tended to have a shorter overall survival (OS) (12.2 vs. 29.9 m, HR = 2.20 [95% CI 0.98–4.91], P = 0.052). Furthermore, RNA-seq and Western blot analyses confirmed that the deletion of SWI/SNF genes resulted in downregulated STING expression in NSCLC cell lines. And IHC analysis of patient tumour samples confirmed that the loss of SWI/SNF protein expression was associated with decreased STING protein levels. Notably, downregulated STING protein expression was observed in KRAS-mut NSCLC patients who did not benefit from ICB treatment.

Conclusions

In KRAS-mut NSCLCs with or without STK11/KEAP1 mutations, the GPAs in the DNA-binding genes ARID1A/ARID2 affected the outcomes of immunotherapy, possibly through the downregulation of STING expression.