Yang Fangfang, Hou Helei, Wang Guanqun, Fu Guangming, Huo Xingfa, Duan Xueqin, Zhou Na, Zhang Xiaochun
Precision Medicine Center of Oncology, The Affiliated Hospital of Qingdao University, Qingdao, China.
Qingdao Medical College, Qingdao University, Qingdao, China.
Front Pharmacol. 2025 May 20;16:1582005. doi: 10.3389/fphar.2025.1582005. eCollection 2025.
Concurrent genetic alterations (e.g., TP53 comutations) significantly impair EGFR-TKI responsiveness and survival outcomes in EGFR-mutant lung adenocarcinoma (LUAD). AT-rich interactive domain 1A (ARID1A), which is a key subunit of SWI/SNF complexes, demonstrates critical regulatory functions as a tumour suppressor gene in cancer. The aim of this study is to determine the role of ARID1A deficiency in the therapeutic efficacy of EGFR-TKIs in LUAD.
We identified the ARID1A mutation as a potential prognostic marker in EGFR-mutant LUAD by analysing data from cBioPortal. The expression of ARID1A was detected via immunohistochemical staining. A lentivirus was employed to construct the ARID1A knockdown model in PC9 cell. We further analyzed the biological roles of ARID1A knockdown through CCK8, flow cytometry analysis and transwell assay.
The ARID1A mutation was associated with poor OS in EGFR-mutant LUAD patients, and the prognostic influence was greater than that of concurrent EGFR mutations with TP53, KRAS, CDKN2A, PIK3CA, RB1 or PTEN. By analysing the clinical data of our centre, we revealed that patients with loss of ARID1A expression demonstrated poorer median progression-free survival (mPFS, 10.3 versus 30 months, = 0.005) when they received EGFR-TKIs as the first-line treatment after postoperative progression (cohort A). A shorter median disease-free survival (mDFS, 29 versus NA months, = 0.003) was also observed in the ARID1A low-expression cohort than in the ARID1A high-expression group in patients receiving postoperative adjuvant EGFR-TKI treatments (cohort B). We also found that ARID1A deficiency attenuated the efficacy of osimertinib by activating the EGFR/AKT/mTOR signalling axis in PC9 cell.
ARID1A deficiency may be an independent prognostic factor and attenuates the response to EGFR-TKIs in patients with EGFR-mutant LUAD. In addition, loss of ARID1A expression confers resistance to EGFR-TKI by activating the EGFR/AKT/mTOR signalling axis.
同时发生的基因改变（如TP53共突变）会显著损害表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）在EGFR突变型肺腺癌（LUAD）中的反应性和生存结果。富含AT的相互作用结构域1A（ARID1A）是SWI/SNF复合物的关键亚基，作为一种肿瘤抑制基因在癌症中发挥着关键的调节功能。本研究的目的是确定ARID1A缺陷在LUAD中EGFR-TKIs治疗效果中的作用。
我们通过分析cBioPortal的数据，将ARID1A突变确定为EGFR突变型LUAD中的一种潜在预后标志物。通过免疫组织化学染色检测ARID1A的表达。使用慢病毒构建PC9细胞中的ARID1A敲低模型。我们通过CCK8、流式细胞术分析和Transwell实验进一步分析了ARID1A敲低的生物学作用。
ARID1A突变与EGFR突变型LUAD患者的总生存期（OS）较差相关，其预后影响大于与TP53、KRAS、CDKN2A、PIK3CA、RB1或PTEN同时发生的EGFR突变。通过分析我们中心的临床数据，我们发现，在术后进展后接受EGFR-TKIs作为一线治疗的患者中，ARID1A表达缺失的患者的中位无进展生存期（mPFS，10.3个月对30个月，P = 0.005）较差（队列A）。在接受术后辅助EGFR-TKI治疗的患者中，ARID1A低表达队列的中位无病生存期（mDFS，29个月对无数据个月，P = 0.003）也比ARID1A高表达组短（队列B）。我们还发现，ARID1A缺陷通过激活PC9细胞中的EGFR/AKT/mTOR信号轴减弱了奥希替尼的疗效。
ARID1A缺陷可能是EGFR突变型LUAD患者的一个独立预后因素，并减弱其对EGFR-TKIs的反应。此外，ARID1A表达缺失通过激活EGFR/AKT/mTOR信号轴赋予对EGFR-TKI的抗性。
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