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.