HER3- A key survival pathway and an emerging therapeutic target in metastatic colorectal cancer and pancreatic ductal adenocarcinoma
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Omkar Desai1,2 and Rui Wang1,2,3
1 Department of Surgery, Case Western Reserve University, Cleveland, OH 44106, USA
2 Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA
3 Department of Surgery, Division of Surgical Oncology, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA
|Rui Wang,||email:||[email protected]|
Keywords: HER3; colorectal; pancreatic cancer; metastasis; microenvironment
Received: March 15, 2023 Accepted: April 24, 2023 Published: May 10, 2023
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.
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