Liver Endothelium Promotes HER3-Mediated Cell Survival in Colorectal Cancer with Wild-Type and Mutant KRAS.

Abstract

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.

IMPLICATIONS:

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.

• Authors: Moeez Rathore, Wei Zhang, Michel'le Wright, Rajat Bhattacharya, Fan Fan, Ali Vaziri-Gohar, Jordan Winter, Zhenghe Wang, Sanford D Markowitz, Joseph Willis, Lee M Ellis, Rui Wang
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 20 Issue 6 Pg. 996-1008 (06 03 2022) ISSN: 1557-3125 [Electronic] United States
• PMID: 35276002 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, N.I.H., Extramural)
• Copyright: ©2022 American Association for Cancer Research.

Chemical References

• KRAS protein, human
• ErbB Receptors
• Proto-Oncogene Proteins p21(ras)

Topics

• Animals
• Cell Survival
• Colorectal Neoplasms (drug therapy, genetics, pathology)
• Endothelium (metabolism, pathology)
• ErbB Receptors (genetics)
• Humans
• Liver (pathology)
• Mice
• Mice, Nude
• Mutation
• Proto-Oncogene Proteins p21(ras) (genetics, metabolism)
• Tumor Microenvironment