PARP抑制增强HER3-DXd在非小细胞肺癌中的抗肿瘤活性
PARP inhibition enhances the antitumor activity of HER3-DXd in non-small cell lung cancer.
作者
作者单位
- Institute of Molecular Medicine Finland (FIMM), Helsinki Institute of Life Sciences (HiLIFE) & Translational Immunology Research Program (TRIMM), Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland; iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Helsinki, Finland.
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Experimental Therapeutics Core and Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Boston, MA, USA.
- iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Helsinki, Finland; Department of General Thoracic and Esophageal Surgery, Heart and Lung Center, Helsinki University Hospital & University of Helsinki, Helsinki, Finland.
- Institute of Molecular Medicine Finland (FIMM), Helsinki Institute of Life Sciences (HiLIFE) & Translational Immunology Research Program (TRIMM), Research Programs Unit, Faculty of Medicine, University of Helsinki, Helsinki, Finland; iCAN Digital Precision Cancer Medicine Flagship, University of Helsinki, Helsinki, Finland; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Center for Cancer Eradication Research, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland; Research Unit, Heart and Lung Center, Helsinki University Hospital, Helsinki, Finland. Electronic address: heidi.haikala@helsinki.fi.
摘要
中文
肺癌是癌症相关死亡的主要原因，通常由关键癌基因表皮生长因子受体（EGFR）和Kirsten大鼠肉瘤病毒（KRAS）的突变驱动。尽管酪氨酸激酶抑制剂等靶向治疗取得了进展，耐药性仍然是一个重大障碍。HER3的过表达与非小细胞肺癌（NSCLC）的不良预后相关，提供了一个替代治疗靶点。在本研究中，我们调查了靶向HER3的抗体药物偶联物HER3-DXd的疗效及其与细胞周期和DNA损伤反应调节剂联合时的协同潜力。观察到与PARP抑制剂显著协同，在EGFR和KRAS突变的NSCLC模型中均有效。这种联合显著增强DNA损伤，诱导凋亡，并减缓体内肿瘤进展。值得注意的是，该方案还通过cGAS-STING通路激活触发抗体依赖性免疫调节效应，增强先天免疫细胞的肿瘤杀伤作用。我们的研究结果表明，HER3-DXd与PARP抑制剂联合提供了一种有前景的治疗方法，有效靶向多种NSCLC亚型。
English
Lung cancer, a leading cause of cancer-related mortality, is often driven by mutations in the key oncogenes epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma virus (KRAS). Despite advancements of targeted therapies such as tyrosine kinase inhibitors, resistance remains a significant hurdle. Overexpression of HER3, associated with poor prognosis in non-small cell lung cancer (NSCLC), presents an alternative therapeutic target. In this study, we investigate the efficacy of the HER3-targeting antibody-drug conjugate HER3-DXd and its synergistic potential when combined with cell cycle and DNA damage response modulators. A significant synergy is observed with PARP inhibitors, effective in both EGFR- and KRAS-mutated NSCLC models. This combination markedly enhances DNA damage, induces apoptosis, and slows down in vivo tumor progression. Notably, this regimen also triggers antibody-dependent immunomodulatory effects through cGAS-STING pathway activation, potentiating innate immune cells for tumor killing. Our findings suggest that combining HER3-DXd with PARP inhibitors offers a promising therapeutic approach, effectively targeting diverse NSCLC subtypes.
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
- 45.1
- 新锐分区
- 1区