MUC1 promotes glioblastoma progression and TMZ resistance by stabilizing EGFRvIII

• DOI: 10.1016/j.phrs.2022.106606
• Publication Date: 2022-12-11T14:38:32Z
• Authors: Fei Tong; Ji-xing Zhao; Zi-yuan Fang; Xiao-teng Cui; Dong-yuan Su; Xing Liu; Jun-hu Zhou; Guang-xiu Wang; Zhi-jun Qiu; Shi-zhong Liu; Jun-qi Fu; Chun-sheng Kang; Jia-chong Wang; Qi-xue Wang
• Keywords: Temozolomide

Epidermal growth factor receptor variant III (EGFRvIII) is a mutant isoform of EGFR with deletion exons 2-7 making it insensitive to EGF stimulation and downstream signal constitutive activation. However, the mechanism underlying stability EGFRvIII remains unclear. Based on CRISPR-Cas9 library screening, we found that mucin1 (MUC1) essential for glioma cell survival temozolomide (TMZ) resistance. We revealed MUC1-C was upregulated in EGFRvIII-positive cells, where enhanced EGFRvIII. Knockdown increased colocalization lysosomes. Upregulation MUC1 occurred an NF-κB dependent manner, inhibition pathway could interrupt EGFRvIII-MUC1 feedback loop by inhibiting MUC1-C. In previous report, identified AC1Q3QWB (AQB), small molecule inhibit phosphorylation NF-κB. By screening structural analogs AQB, obtained EPIC-1027, which more effectively. EPIC-1027 disrupted EGFRvIII-MUC1-C positive vitro vivo, inhibited progression, promoted sensitization TMZ. conclusion, pivotal role stabilizing glioblastoma (GBM) molecule, great potential GBM treatment.