کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
11023055 | 1701347 | 2018 | 31 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Inducible SHP-2 activation confers resistance to imatinib in drug-tolerant chronic myeloid leukemia cells
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کلمات کلیدی
موضوعات مرتبط
علوم زیستی و بیوفناوری
علوم محیط زیست
بهداشت، سم شناسی و جهش زایی
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چکیده انگلیسی
BCR-ABL kinase mutations, accounting for clinical resistance to tyrosine kinase inhibitor (TKI) such as imatinib, frequently occur in acquired resistance or in advanced phases of chronic myeloid leukemia (CML). Emerging evidence implicates a critical role for non-mutational drug resistance mechanisms underlying the survival of residual cancer 'persister' cells. Here, we utilized non-mutational imatinib-resistant K562/G cells to reveal SHP-2 as a resistance modulator of imatinib treatment response during the early phase. SHP-2 phosphorylation was significantly higher in K562/G cells than in sensitive K562 cells. In K562 cells, both short-term and long-term exposure to imatinib induced SHP-2 phosphorylation. Consistently, gain- and loss-of-function mutants in SHP-2 proved its regulation of imatinib resistance. SHP-2 inhibitor and imatinib exhibited a strong antitumor synergy in in vitro and in vivo K562/G models. Mechanistically, dual SHP-2 and BCR-ABL inhibition blocked RAF/MEK/ERK and PI3K/AKT/mTOR pathways, respectively, leading to dramatic apoptotic death of K562/G cells. In conclusion, our results highlight that SHP-2 could be exploited as a biomarker and therapeutic target during the early phase of imatinib resistance development in CML.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Toxicology and Applied Pharmacology - Volume 360, 1 December 2018, Pages 249-256
Journal: Toxicology and Applied Pharmacology - Volume 360, 1 December 2018, Pages 249-256
نویسندگان
Xin Li, Juan Pang, Wenwen Xue, Yixuan Wang, Tian Tian, Ahmed Elgehama, Xuefeng Wu, Xudong Wu, Yang Sun, Hongxia Qiu, Yan Shen, Qiang Xu,