支原体感染通过趋同的转录组重编程驱动非小细胞肺癌的EGFR-TKI耐药
Mycoplasma infection drives EGFR-TKI resistance through convergent transcriptomic reprogramming in non-small cell lung cancer.
作者
作者单位
- Department of Medical Oncology, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, the Netherlands.
- Cancer Pharmacology Lab, Fondazione Pisana per la Scienza, San Giuliano, Pisa, Italy.
- Department of Preventive Dentistry, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
摘要
中文
表皮生长因子受体（EGFR）突变是非小细胞肺癌（NSCLC）的致癌驱动因素，但对EGFR酪氨酸激酶抑制剂（TKIs）的耐药仍是主要挑战。在这里，我们显示支原体感染维持ERK、AKT和NF-κB信号传导；损害受体内部化；并降低EGFR突变NSCLC细胞对奥希替尼的敏感性。抗生素介导的支原体清除部分恢复了药物敏感性，建立了因果性的感染-耐药联系。转录组分析确定了与支原体感染和药物耐药相关的趋同通路，包括抑制受体内部化和网格蛋白蛋白水平下调的基因集富集。mTOR和LDHA的联合抑制改善了支原体阳性细胞的生长抑制。临床上，支原体感染和较高的LDHA表达与接受EGFR-TKI治疗的患者总生存期较差相关。这些发现确立了支原体感染作为EGFR-TKI耐药的因果性非遗传因素，并支持将抗生素根除与mTOR和LDHA抑制相结合的层级治疗策略。
English
Epidermal growth factor receptor (EGFR) mutations are an oncogenic driver in non-small cell lung cancer (NSCLC), but resistance to EGFR tyrosine kinase inhibitors (TKIs) remains a major challenge. Here, we show that mycoplasma infection sustains ERK, AKT, and NF-κB signaling; impairs receptor internalization; and reduces osimertinib sensitivity in EGFR-mutant NSCLC cells. Antibiotic-mediated clearance of Mycoplasma partially restored drug sensitivity, establishing a causal infection-resistance link. Transcriptomic analysis identified converging pathways related to mycoplasma infection and drug resistance, including gene sets enriched for inhibition of receptor internalization and clathrin downregulation at the protein level. Combined inhibition of mTOR and LDHA improved growth suppression in mycoplasma-positive cells. Clinically, mycoplasma infection and higher LDHA expression were associated with poor overall survival of EGFR-TKI-treated patients. These findings establish mycoplasma infection as a causal, non-genetic contributor to EGFR-TKI resistance and support a hierarchical therapeutic strategy combining antibiotic eradication with mTOR and LDHA inhibition.
分类与指标
- 研究类型
- 基础研究
- 病种
- 肺癌
- JCR 分区
- Q1
- 影响因子
- 4.5
- 新锐分区
- 3区