Moreover, we determined that blocking HER3, either by siRNA knockdown or the humanized antibody seribantumab, blocked EC-induced CRC survival in vitro in both KRAS wild-type and mutant CRC cells, and the HER3 antibody seribantumab significantly decreased CRC tumor growth and sensitized tumors to chemotherapy in an orthotopic xenograft model with CRC tumors developed in the liver. 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 mCRC.