Department of Surgery, Case Western Reserve University, Cleveland, OH 44106, USA.
Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA.
Oncotarget. 2023 May 10;14:439-443. doi: 10.18632/oncotarget.28421.
Colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) are highly metastatic cancers with poor survival rates. The tumor microenvironment has been shown to play a critical role in cancer progression and response to therapies. Endothelial cells (ECs) are a key component of the tumor microenvironment and promote cancer cell survival by secreting soluble factors that activate cancer-promoting signaling pathways. Studies from us and others identified HER3 as a key mediator of liver EC-induced chemoresistance and cancer cell growth in metastatic CRC and PDAC. In this article, we discuss that HER3-targeted therapies may be effective in treating patients with HER3-expressing CRC and PDAC, and highlight the importance of applying HER3 expression as a predictive biomarker for patient response to HER3-targeted therapies. We also discuss the challenges encountered in past clinical trials of HER3-targeted therapies, including the role of gene fusions, alternative HER3 activation mechanisms, and adaptive resistance mechanisms. Finally, we conclude by suggesting the future directions of HER3-targeted therapies, including novel approaches to overcome chemoresistance and promote cancer cell death.
结直肠癌（CRC）和胰腺导管腺癌（PDAC）是高度转移性癌症，生存率低。肿瘤微环境已被证明在癌症进展和对治疗的反应中起着关键作用。内皮细胞（ECs）是肿瘤微环境的关键组成部分，通过分泌激活促进癌症的信号通路的可溶性因子来促进癌细胞存活。我们和其他人的研究确定 HER3 是肝 EC 诱导的转移性 CRC 和 PDAC 中的化疗耐药性和癌细胞生长的关键介质。在本文中，我们讨论了针对 HER3 的治疗方法可能对治疗表达 HER3 的 CRC 和 PDAC 患者有效，并强调了将 HER3 表达作为预测生物标志物用于预测患者对 HER3 靶向治疗的反应的重要性。我们还讨论了过去针对 HER3 的治疗临床试验中遇到的挑战，包括基因融合、HER3 激活的替代机制和适应性耐药机制的作用。最后，我们通过提出针对 HER3 的治疗方法的未来方向来总结，包括克服化疗耐药性和促进癌细胞死亡的新方法。
