Department of Surgery, Case Western Reserve University, Cleveland, Ohio.
Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.
Mol Cancer Res. 2022 Jun 3;20(6):996-1008. doi: 10.1158/1541-7786.MCR-21-0633.
We previously identified that human epidermal growth factor receptor 3 (HER3, also known as ERBB3) is a key mediator in liver endothelial cell (EC) promoting colorectal cancer growth and chemoresistance, and suggested HER3-targeted therapy as a strategy for treating patients with metastatic colorectal cancer in the liver. Meanwhile, KRAS mutations occur in 40%-50% of metastatic colorectal cancer and render colorectal cancer resistant to therapies targeting the other HER family protein epidermal growth factor receptor (EGFR). It is necessary to elucidate the roles of KRAS mutation status in HER3-mediated cell survival and colorectal cancer response to HER3 inhibition. In the present study, we used primary ECs isolated from non-neoplastic liver tissues to recapitulate the liver EC microenvironment. We demonstrated that liver EC-secreted factors activated colorectal cancer-associated HER3, and increased colorectal cancer cell survival in vitro and promoted colorectal cancer patient-derived xenograft tumor growth in vivo. Moreover, we determined that blocking HER3, either by siRNA knockdown or the humanized antibody seribantumab, blocked EC-induced colorectal cancer survival in vitro in both KRAS wild-type and mutant colorectal cancer cells, and the HER3 antibody seribantumab significantly decreased colorectal cancer tumor growth and sensitized tumors to chemotherapy in an orthotopic xenograft model with colorectal cancer tumors developed in the liver. In summary, our findings demonstrated that blocking HER3 had significant effects on attenuating liver EC-induced colorectal cancer cell survival independent of the KRAS mutation status.
This body of work highlighted a potential strategy of using HER3 antibodies in combination with standard chemotherapy agents for treating patients with either KRAS wild-type or KRAS mutant metastatic colorectal cancer.
我们之前发现，人表皮生长因子受体 3（HER3，也称为 ERBB3）是促进结直肠癌细胞生长和化疗耐药的肝内皮细胞（EC）的关键介质，并提出针对 HER3 的靶向治疗是治疗肝转移结直肠癌患者的一种策略。同时，KRAS 突变发生在 40%-50%的转移性结直肠癌中，使结直肠癌对针对其他 HER 家族蛋白表皮生长因子受体（EGFR）的治疗产生耐药性。有必要阐明 KRAS 突变状态在 HER3 介导的细胞存活和结直肠癌对 HER3 抑制的反应中的作用。在本研究中，我们使用从非肿瘤性肝组织中分离的原代 EC 来重现肝 EC 微环境。我们证明肝 EC 分泌的因子激活了与结直肠癌相关的 HER3，并在体外增加了结直肠癌细胞的存活，并促进了结直肠癌患者衍生的异种移植肿瘤在体内的生长。此外，我们确定通过 siRNA 敲低或人源化抗体 seribantumab 阻断 HER3，可阻断 EC 诱导的 KRAS 野生型和突变型结直肠癌细胞在体外的结直肠癌细胞存活，并且 HER3 抗体 seribantumab 显著降低了结直肠癌肿瘤生长，并在结直肠癌肿瘤在肝脏中发展的原位异种移植模型中使肿瘤对化疗敏感。总之，我们的研究结果表明，阻断 HER3 对减轻肝 EC 诱导的结直肠癌细胞存活具有显著作用，而与 KRAS 突变状态无关。
这项工作强调了一种潜在的策略，即使用 HER3 抗体与标准化疗药物联合治疗 KRAS 野生型或 KRAS 突变型转移性结直肠癌患者。
