MUC1 promotes glioblastoma progression and TMZ resistance by stabilizing EGFRvIII

  • Pharmacol Res. 2022 Dec 11;187:106606. doi: 10.1016/j.phrs.2022.106606.
Fei Tong  1 ,  Ji-Xing Zhao  1 ,  Zi-Yuan Fang  2 ,  Xiao-Teng Cui  1 ,  Dong-Yuan Su  1 ,  Xing Liu  3 ,  Jun-Hu Zhou  1 ,  Guang-Xiu Wang  1 ,  Zhi-Jun Qiu  4 ,  Shi-Zhong Liu  4 ,  Jun-Qi Fu  5 ,  Chun-Sheng Kang  6 ,  Jia-Chong Wang  7 ,  Qi-Xue Wang  8
Affiliations
  • 1. Tianjin Medical University General Hospital, Tianjin 300052, China; Tianjin Neurological Institute, Key Laboratory of Neurotrauma, Variation, and Regeneration, Ministry of Education and Tianjin Municipal Government, Tianjin 300052, China.
  • 2. Clinical Medical College, Hebei University, Baoding 071000, China.
  • 3. Beijing Neurosurgical Institute, Capital Medical University, Beijing 100050, China.
  • 4. Tianjin Medical University General Hospital, Tianjin 300052, China.
  • 5. Department of Neurosurgery, Haikou Affiliated Hospital of Xiangya Medical College, Central South University, Hainan 570311, China; Department of Neurosurgery, Haikou People's Hospital, Hainan 570208, China.
  • 6. Tianjin Medical University General Hospital, Tianjin 300052, China; Tianjin Neurological Institute, Key Laboratory of Neurotrauma, Variation, and Regeneration, Ministry of Education and Tianjin Municipal Government, Tianjin 300052, China. Electronic address: [email protected].
  • 7. Department of Neurosurgery, Haikou Affiliated Hospital of Xiangya Medical College, Central South University, Hainan 570311, China; Department of Neurosurgery, Haikou People's Hospital, Hainan 570208, China. Electronic address: [email protected].
  • 8. Tianjin Medical University General Hospital, Tianjin 300052, China; Tianjin Neurological Institute, Key Laboratory of Neurotrauma, Variation, and Regeneration, Ministry of Education and Tianjin Municipal Government, Tianjin 300052, China. Electronic address: [email protected].
PMID: 36516884 DOI: 10.1016/j.phrs.2022.106606
Abstract

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-κB dependent manner, and inhibition of the NF-κB 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-κB. By screening the structural analogs of AQB, we obtained EPIC-1027, which could inhibit the NF-κB 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.

Keywords
EPIC-1027; Epidermal growth factor receptor variant III; Glioblastoma; Mucin 1-C; NF-κB.
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