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DNMT3A governs tyrosine kinase inhibitors responses through IAPs and in a cell senescence-dependent manner in non-small cell lung cancer.
Deng, Qin-Fang; Li, Chao; Liu, Jing; Ji, Xian-Xiu; Wan, Xiao-Ying; Wang, Chun-Yan; Sun, Hui; Fang, Qi-Yu; Gu, Wei-Qin; Ma, Chao; Wang, Hui-Yong; Zhou, Cai-Cun; Li, Yi-Xue; Xie, Bo-Xiong; Zhou, Song-Wen.
Afiliación
  • Deng QF; Department of Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine Shanghai, China.
  • Li C; Smartquerier Gene Technology (Shanghai) Co., Ltd. Shanghai, China.
  • Liu J; Shanghai Engineering Research Center of Pharmaceutical Translation Shanghai, China.
  • Ji XX; Shanghai Institute for Biomedical and Pharmaceutical Technologies Shanghai, China.
  • Wan XY; Smartquerier Gene Technology (Shanghai) Co., Ltd. Shanghai, China.
  • Wang CY; Shanghai Engineering Research Center of Pharmaceutical Translation Shanghai, China.
  • Sun H; Shanghai Institute for Biomedical and Pharmaceutical Technologies Shanghai, China.
  • Fang QY; Department of Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine Shanghai, China.
  • Gu WQ; Department of Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine Shanghai, China.
  • Ma C; Department of Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine Shanghai, China.
  • Wang HY; Department of Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine Shanghai, China.
  • Zhou CC; Department of Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine Shanghai, China.
  • Li YX; Department of Oncology, Shanghai Pulmonary Hospital, Tongji University School of Medicine Shanghai, China.
  • Xie BX; Smartquerier Gene Technology (Shanghai) Co., Ltd. Shanghai, China.
  • Zhou SW; Shanghai Engineering Research Center of Pharmaceutical Translation Shanghai, China.
Am J Cancer Res ; 13(8): 3517-3530, 2023.
Article en En | MEDLINE | ID: mdl-37693159
Patients with non-small cell lung cancer (NSCLC) treated with tyrosine kinase inhibitors (TKIs) inevitably exhibit drug resistance, which diminishes therapeutic effects. Nonetheless, the molecular mechanisms of TKI resistance in NSCLC remain obscure. In this study, data from clinical and TCGA databases revealed an increase in DNMT3A expression, which was correlated with a poor prognosis. Using NSCLC organoid models, we observed that high DNMT3A levels reduced TKI susceptibility of NSCLC cells via upregulating inhibitor of apoptosis proteins (IAPs). Simultaneously, the DNMT3Ahigh subset, which escaped apoptosis, underwent an early senescent-like state in a CDKN1A-dependent manner. Furthermore, the cellular senescence induced by TKIs was observed to be reversible, whereas DNMT3Ahigh cells reacquired their proliferative characteristics in the absence of TKIs, resulting in subsequent tumour recurrence and growth. Notably, the blockade of DNMT3A/IAPs signals enhanced the efficacy of TKIs in DNMT3Ahigh tumour-bearing mice, which represented a promising strategy for the effective treatment of NSCLC.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: Am J Cancer Res Año: 2023 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: Am J Cancer Res Año: 2023 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos