The EGF domains of MUC4 oncomucin interact with ErbB2 and mediate tumorigenic activity of cancer cells represent new potential therapeutic targets

Abstract

The MUC4 mucin and its membrane partner ErbB2 form an oncogenic complex at the surface of epithelial cancer cells that promotes tumor progression. They directly physically interact via an extracellular region of MUC4 encompassing three EGF domains opening the route to therapeutic targeting of ErbB2 over‐expressing cancers in which MUC4‐ErbB2 is present. However, before small inhibitory molecules may be designed, it is mandatory (i) to decipher at the molecular level which amino acid regions are involved in the interaction and (ii) show that they mediate cancer cell tumorigenicity. By using in vitro (2D cell culture, Micro Scale Thermophoresis, PLA assay, Co‐IP, GST pull down, Molecular Dynamics simulations) and in vivo (xenograft model of pancreatic cancer) approaches, we show that the EGF1 domain of MUC4 is central both in the interaction with ErbB2 and in the activation of cell proliferation and migration and tumor growth via activation of key oncogenic pathways (Src, Ras, p70S6K/AKT/mTOR, beta‐catenin, FAK). Finally, we have identified hotspots of interaction paving the way to the design of therapeutic inhibitory molecules targeting the EGF domains of MUC4 which may represent a new alternative strategy to overcome ErbB2 therapeutic failure in cancer.

The EGF Domains of MUC4 Oncomucin Mediate HER2 Binding Affinity and Promote Pancreatic Cancer Cell Tumorigenesis

“…A big challenge in this approach will be to overcome the fact that MUC4 is heavily glycosylated and creates a steric hindrance that has already been shown to hamper access of therapeutic antibodies targeting HER2 [ 19 , 20 , 21 , 22 ]. In the past few years, we started to decipher the molecular mechanism of interaction between MUC4 and HER2 and revealed the druggability of the PPI interface as a promising therapeutic target [ 8 , 23 , 24 ]. In addition to showing that endogenous MUC4 directly interacts with HER2 in PC cell lines ( Supplementary Materials Figure S1A,B ), we quantified the binding affinity between MUC4β and HER2 using microscale thermophoresis and showed that the interaction is mediated by the three EGF domains [ 25 ].…”