論文

査読有り 国際誌
2014年11月1日

Targeting the oncogenic MUC1-C protein inhibits mutant EGFR-mediated signaling and survival in non-small cell lung cancer cells.

Clinical cancer research : an official journal of the American Association for Cancer Research
  • Akriti Kharbanda
  • ,
  • Hasan Rajabi
  • ,
  • Caining Jin
  • ,
  • Jeremy Tchaicha
  • ,
  • Eiki Kikuchi
  • ,
  • Kwok-Kin Wong
  • ,
  • Donald Kufe

20
21
開始ページ
5423
終了ページ
34
記述言語
英語
掲載種別
DOI
10.1158/1078-0432.CCR-13-3168

PURPOSE: Non-small cell lung cancers (NSCLC) that express EGF receptor with activating mutations frequently develop resistance to EGFR kinase inhibitors. The mucin 1 (MUC1) heterodimeric protein is aberrantly overexpressed in NSCLC cells and confers a poor prognosis; however, the functional involvement of MUC1 in mutant EGFR signaling is not known. EXPERIMENTAL DESIGN: Targeting the oncogenic MUC1 C-terminal subunit (MUC1-C) in NSCLC cells harboring mutant EGFR was studied for effects on signaling, growth, clonogenic survival, and tumorigenicity. RESULTS: Stable silencing of MUC1-C in H1975/EGFR(L858R/T790M) cells resulted in downregulation of AKT signaling and inhibition of growth, colony formation, and tumorigenicity. Similar findings were obtained when MUC1-C was silenced in gefitinib-resistant PC9GR cells expressing EGFR(delE746_A750/T790M). The results further show that expression of a MUC1-C(CQC → AQA) mutant, which blocks MUC1-C homodimerization, suppresses EGFR(T790M), AKT and MEK → ERK activation, colony formation, and tumorigenicity. In concert with these results, treatment of H1975 and PC9GR cells with GO-203, a cell-penetrating peptide that blocks MUC1-C homodimerization, resulted in inhibition of EGFR, AKT, and MEK → ERK signaling and in loss of survival. Combination studies of GO-203 and afatinib, an irreversible inhibitor of EGFR, further demonstrate that these agents are synergistic in inhibiting growth of NSCLC cells harboring the activating EGFR(T790M) or EGFR(delE746-A750) mutants. CONCLUSIONS: These findings indicate that targeting MUC1-C inhibits mutant EGFR signaling and survival, and thus represents a potential approach alone and in combination for the treatment of NSCLCs resistant to EGFR kinase inhibitors.

リンク情報
DOI
https://doi.org/10.1158/1078-0432.CCR-13-3168
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/25189483
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4219601

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