Dual‐targeting therapy against HER3/MET in human colorectal cancers

• Published in: Cancer medicine (Malden, MA) Vol. 12; no. 8; pp. 9684 - 9696
• Main Authors: Yamasaki, Akitaka, Miyake, Rikuto, Hara, Yuta, Okuno, Hideki, Imaida, Takuya, Okita, Kouki, Okazaki, Shogo, Akiyama, Yasutoshi, Hirotani, Kenji, Endo, Yuichi, Masuko, Kazue, Masuko, Takashi, Tomioka, Yoshihisa
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.04.2023; John Wiley and Sons Inc; Wiley
• Subjects: Animals; Antibodies; c-Met protein; Cancer therapies; Cell culture; Cell Line, Tumor; Cell Proliferation; Cell surface; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Forkhead Box protein M1; Forkhead protein; Glycerol; Growth factors; Hepatocyte growth factor; human epidermal growth factor receptor family; Humans; Immunohistochemistry; Kinases; Laboratory animals; Malignancy; Membrane proteins; Membranes; mesenchymal to epithelial transition factor; Mice; Mice, Nude; Neuregulin 1; Phosphorylation; Proteins; Signal Transduction; Tumors; Tyrosine; United States > US; Japan; human epidermal growth factor receptor family; Forkhead Box protein M1; colorectal cancer; mesenchymal to epithelial transition factor
• ISSN: 2045-7634; 2045-7634
• DOI: 10.1002/cam4.5673

Background Colorectal cancer (CRC) is the most common malignancy in the world, and novel molecular targeted therapies for CRC have been vigorously pursued. We searched for novel combination therapies based on the expression patterns of membrane proteins in CRC cell lines. Results A positive correlation was observed between the expression of human pidermal growth factor receptor (HER) 3 and mesenchymal‐to‐epithelial transition factor (MET) on the cell surface of CRC cell lines. The brief stimulation of HER3/MET‐high SW1116 CRC cells with both neuregulin‐1 (NRG1) and hepatocyte growth factor enhanced ERK phosphorylation and cell proliferation more than each stimulation alone. In addition, a prolonged NRG1 stimulation resulted in the tyrosine phosphorylation of MET. In this context, the Forkhead Box protein M1 (FOXM1)‐regulated tyrosine phosphorylation of MET by NRG1 was demonstrated, suggesting the existence of a signaling pathway mediated by FOXM1 upon the NRG1 stimulation. Since the co‐expression of HER3 and MET was also demonstrated in in vivo CRC tissues by immunohistochemistry, we investigated whether the co‐inhibition of HER3 and MET could be an effective therapy for CRC. We established HER3‐and/or MET‐KO SW1116 cell lines, and HER3/MET‐double KO resulted in the inhibition of in vitro cell proliferation and in vivo tumor growth in nude mice by SW1116 cells. Furthermore, the combination of patritumab, an anti‐HER3 fully human mAb, and PHA665752, a MET inhibitor, markedly inhibited in vitro cell proliferation, 3D‐colony formation, and in vivo tumor growth in nude mice by SW1116 cells Conclusion The dual targeting of HER3/MET has potential as CRC therapy. The present study demonstrated that HER3 and MET were not directly associated with each other in CRC but cooperated for the cellular and tumor growth of CRC. In this context, the combination of anti‐HER3 (patritumab) and anti‐MET (PHA665752) drugs was definitely effective against HER3/MET‐high SW1116 CRC cells, indicating the potential of the dual inhibition of HER3 and MET as targeting therapy in human CRC.