HER3- A key survival pathway and an emerging therapeutic target in metastatic colorectal cancer and pancreatic ductal adenocarcinoma.
HER3- A key survival pathway and an emerging therapeutic target in metastatic colorectal cancer and pancreatic ductal adenocarcinoma.
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结直肠癌(CRC)和胰腺导管腺癌(PDAC)是高转移性癌症，生存率较低。肿瘤微环境已被证明在癌症进展和治疗反应中起关键作用。内皮细胞(ECs)是肿瘤微环境的重要组成部分，通过分泌可溶性因子激活促癌信号通路，促进肿瘤细胞存活。我们和其他人的研究证实，HER3是转移性结直肠癌和PDAC中肝EC诱导的化疗耐药和癌细胞生长的关键介质。在这篇文章中，我们讨论了HER3靶向治疗在治疗HER3表达的结直肠癌和PDAC患者中可能是有效的，并强调了应用HER3表达作为预测患者对HER3靶向治疗反应的生物标志物的重要性。我们还讨论了在过去针对HER3的治疗的临床试验中遇到的挑战，包括NRG1基因融合的作用，替代的HER3激活机制，以及适应性耐药机制。最后，我们提出了HER3靶向治疗的未来方向，包括克服化疗耐药和促进癌细胞死亡的新方法。
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 NRG1 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.