Liver endothelium promotes HER3-mediated cell survival in KRAS wild-type and mutant colorectal cancer cells

We previously showed that primary liver endothelial cells (ECs) secreted soluble factors in a paracrine fashion (angiocrine) and activated human epidermal growth factor receptor 3 (HER3, also known as ERBB3) mediated colorectal cancer (CRC) growth and chemoresistance. However, Ras proteins play a critical role in receptor tyrosine kinase signaling pathways, and KRAS mutations mediate CRC resistance to therapies targeting EGFR, another HER protein. Therefore, the role of KRAS mutation status in EC-induced HER3 activation and CRC survival was investigated as it has therapeutic implications. We used CRC cell lines and patient-derived xenografts harboring KRAS wild-type or mutant genes and demonstrated that liver EC-secreted factors promoted HER3-mediated CRC cell growth independent of KRAS mutation status. Also, blocking HER3 in CRC by siRNAs or a HER3 antibody seribantumab attenuated EC-induced CRC cell survival. Our findings highlight the potential of utilizing HER3-targeted therapies for treating patients with mCRC independent of RAS mutational status