Huang Qiaoxin, He Shengsong, Zhan Dongang
Department of Infectious Diseases, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, China.
Department of Infectious Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
J Cancer Res Clin Oncol. 2023 Sep;149(12):10727-10735. doi: 10.1007/s00432-023-04926-5. Epub 2023 Jun 13.
To investigate the effects of osimertinib on hepatocellular carcinoma (HCC) and angiogenesis, and its combinatory effects with venetoclax in HCC.
Viability was assessed by flow cytometry of Annexin V in multiple HCC cell lines after drug treatment. In vitro angiogenesis assay was performed using primary human liver tumor associated endothelial cell (HLTEC). HCC-bearing model was generated by subcutaneous implantation of Hep3B cells to investigate the efficacy of osimertinib alone and its combination with venetoclax.
Osimertinib significantly induced apoptosis in a panel of HCC cell lines regardless of EGFR expression level. It inhibited capillary network formation and induced apoptosis in HLTEC. Using HCC xenograft mouse model, we further showed that osimertinib at non-toxic dose inhibited tumor growth by ~ 50% and remarkably decreased blood vessel in tumor. Mechanism studies demonstrated that osimertinib acted on HCC cells in an EGFR-independent manner. It decreased level of VEGF and Mcl-1 in HCC cells via suppressed phosphorylation of eIF4E, thus leading to inhibition of eIF4E-mediated translation. Mcl-1 overexpression reversed pro-apoptotic effect of osimertinib, suggesting an important role of Mcl-1 in osimertinib's action in HCC cells. Of note, the combination of osimertinib and venetoclax achieved approximately complete HCC cell death and tumor growth in mice.
We provide pre-clinical evidence that osimertinib is a promising candidate for the treatment of HCC via targeting tumor cells and angiogenesis. The combination of osimertinib and venetoclax is synergistic in inhibiting HCC.
研究奥希替尼对肝细胞癌（HCC）和血管生成的影响，以及其与维奈克拉联合应用于HCC的效果。
通过药物处理后对多种HCC细胞系进行Annexin V流式细胞术评估细胞活力。使用原代人肝肿瘤相关内皮细胞（HLTEC）进行体外血管生成测定。通过皮下植入Hep3B细胞建立荷HCC模型，以研究奥希替尼单独应用及其与维奈克拉联合应用的疗效。
无论EGFR表达水平如何，奥希替尼均能显著诱导一组HCC细胞系凋亡。它抑制HLTEC中的毛细血管网络形成并诱导凋亡。使用HCC异种移植小鼠模型，我们进一步表明，无毒剂量的奥希替尼可抑制肿瘤生长约50%，并显著减少肿瘤中的血管。机制研究表明，奥希替尼以EGFR非依赖性方式作用于HCC细胞。它通过抑制eIF4E的磷酸化降低HCC细胞中VEGF和Mcl-1的水平，从而导致对eIF4E介导的翻译的抑制。Mcl-1过表达逆转了奥希替尼的促凋亡作用，表明Mcl-1在奥希替尼对HCC细胞的作用中起重要作用。值得注意的是，奥希替尼和维奈克拉联合应用可使小鼠体内的HCC细胞几乎完全死亡并抑制肿瘤生长。
我们提供了临床前证据，表明奥希替尼通过靶向肿瘤细胞和血管生成是治疗HCC的有前景的候选药物。奥希替尼和维奈克拉联合应用在抑制HCC方面具有协同作用。
