The Mechanism Of MUC16 Promotes Cell Drug Resistance To HER2 Inhibitor

HER2 is a member of the human epidermal growth factor receptor family and an important tumor marker for clinical diagnosis and treatment of breast and ovarian cancer.HER2 can form heterodimers with other members of the HER family,and activate its downstream signaling pathways.It has also been found that HER2 overexpression happens in human cancers such as breast cancer,ovarian cancer and lung cancer,which plays an important role in tumorigenesis and development.Clinical data show that patients with HER2 overexpression may develop primary or acquired resistance after treating with HER2 inhibitors.At present,the drug resistance to HER2 inhibitors is a difficult problem in cancer treatment.Therefore,it is very important to investigate the mechanism of drug resistance to HER2 inhibitors for effective treatment of cancers.It was found that MUC1 and MUC4 of mucin family can interact with HER2.MUC1 can promote HER2 phosphorylation to resist the treatment of HER2 inhibitors.The combination of MUC4 and HER2 can hinder the recognition of trastuzumab.MUC4 can also increase HER2 expression and activate the downstream signaling pathways of HER2.MUC16 is also known as the member of mucin family,it is the largest glycoprotein in the mucin family.Studies have found that MUC16 can promote the occurrence and development of tumors,and it is over-expressed in ovarian,breast,cervical,lung and colon cancers.MUC16 is similar to MUC1 in function,whether MUC16 can interact with HER2?Does it also affect the expression or phosphorylation of HER2?Can it promote cell drug resistnce to HER2 inhibitors?Firstly,we found that MUC16 could interact with HER2 and co-localize on the cell membrane.Next,we found that MUC16 could promote HER2 phosphorylation and PI3K/AKT signaling pathway,but had no effect on HER2 expression.Finally,we found that MUC16 could promote cell proliferation by activating HER2 and PI3K/AKT signaling pathway,thus promote cell drug resistance to HER2 inhibitors.In conclusion,MUC16 can promote cell drug resistance to HER2 inhibitors by activating HER2 signaling pathway.Therefore,dual therapy of targeting MUC16 and HER2 is expected to reduce patient drug resistance to HER2 inhibitors,and its effectiveness needs further clinical study to verify.