Inducible SHP-2 activation confers resistance to imatinib in drug-tolerant chronic myeloid leukemia cells
Inducible SHP-2 activation confers resistance to imatinib in drug-tolerant chronic myeloid leukemia cells
复制标题
诱导性 SHP-2 激活赋予耐药慢性粒细胞白血病细胞对伊马替尼的耐药性。
DOI：
10.1016/j.taap.2018.09.044
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发表时间：
2018-12-01
影响因子：
3.8
通讯作者：
Xu, Qiang
中科院分区：
文献类型：
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作者：
Li, Xin;Pang, Juan;Xu, Qiang
BCR-ABL激酶突变是导致对酪氨酸激酶抑制剂（TKI）（如伊马替尼）临床耐药的原因，常发生在获得性耐药或慢性粒细胞白血病（CML）晚期。新出现的证据表明，非突变耐药机制在残留癌细胞存活中起着关键作用。在这里，我们利用非突变伊马替尼耐药K562/G细胞，揭示SHP-2作为伊马替尼治疗反应的早期阶段的电阻调制器。K562/G细胞中SHP-2磷酸化水平明显高于敏感细胞。在K562细胞中，短期和长期暴露于伊马替尼诱导SHP-2磷酸化。SHP-2中一致的、获得和丧失功能的突变体证明了其对伊马替尼抗性的调节。SHP-2抑制剂和伊马替尼在体外和体内K562/G模型中表现出很强的抗肿瘤协同作用。从机制上讲，SHP-2和BCR-ABL双重抑制分别阻断了RAF/MEK/ ERK和PI 3 K/AKT/mTOR通路，导致K562/G细胞的急剧凋亡死亡。总之，我们的研究结果强调，SHP-2可以作为一个生物标志物和治疗靶点在伊马替尼耐药发展的早期阶段在CML。
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.