MUC1 promotes glioblastoma progression and TMZ resistance by stabilizing EGFRvIII

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

Automated summary

Based on CRISPR-Cas9 library screening, we found that MUC1-C is essential for EGFRvIII glioma cell survival and TMZ resistance. By inhibiting the NF-kappa B pathway, EPIC-1027 disrupts the EGFRvIII-MUC1-C positive feedback loop, inhibits glioma progression, and increases sensitivity to TMZ.