Oncogenic activity of MAN2A1-FER fusion in liver cancer and other human malignancies

Oncogenic fusion gene is one of the fundamental mechanisms driving the progression of human cancers. MAN2A1‐FER, a fusion gene between the mannosidase domain of MAN2A1 and tyrosine kinase domain of FER, was found in 6 different types of human malignancies. MAN2A1‐FER fusion translocated FER domain from cytoplasm to Golgi apparatus, and led to phosphorylation of N‐terminus of EGFR and activation of EGFR signaling pathway. Expression of MAN2A1‐FER generated dramatic increase of growth and invasion of cancers, while removal of MAN2A1‐FER through knockout generated significant lower level of growth and metastasis. The presence of MAN2A1‐FER increased the sensitivity of human cancers to FER kinase inhibitor crizotinib or EGFR kinase inhibitor canertinib. Hydrodynamic tail‐vein injection of MAN2A1‐FER gene resulted in rapid development of liver cancer in mice with somatic Pten deletion. Taken together, we concluded that MAN2A1‐FER fusion gene is one of the key drivers for human cancer development. Support or Funding Information NCI, DOD and UPCI