Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib-induced KIT mutations in gastrointestinal stromal tumours.
Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib-induced KIT mutations in gastrointestinal stromal tumours.
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尼达尼布克服了胃肠道间质瘤中 FGFR 信号上调和伊马替尼诱导的 KIT 突变带来的耐药性
DOI：
10.1002/1878-0261.13199
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发表时间：
2022-04
影响因子：
6.6
通讯作者：
Liu, Jing
中科院分区：
文献类型：
--
作者：
Liu, Juan;Gao, Jingjing;Wang, Aoli;Jiang, Zongru;Qi, Shuang;Qi, Ziping;Liu, Feiyang;Yu, Kailin;Cao, Jiangyan;Chen, Cheng;Hu, Chen;Wu, Hong;Wang, Li;Wang, Wenchao;Liu, Qingsong;Liu, Jing
耐药性仍然是胃肠道间质瘤（GIST）临床治疗的主要挑战。虽然肥大/干细胞生长因子受体（KIT）激酶的获得性靶向突变是主要的耐药机制，但替代信号通路的激活也可能发挥作用。尽管已经开发出几种第二代和第三代 KIT 激酶抑制剂，可以克服一些 KIT 突变带来的耐药性，但临床反应低和安全窗窄限制了它们的广泛应用。本研究表明，尼达尼布不仅克服了由一系列 KIT 初级和次级突变引起的耐药性，而且还克服了由成纤维细胞生长因子（FGF）活性上调引起的 ERK 重新激活介导的耐药性。在 GIST 的临床前模型中，尼达尼布显着抑制伊马替尼耐药细胞的增殖，包括 GIST-5R、GIST-T1/T670I 和 GIST 患者来源的原代细胞。此外，它还表现出对 FGF 配体刺激时 ERK 磷酸化的剂量依赖性抑制。在几种异种移植胃肠道间质瘤模型中也观察到了体内抗肿瘤活性。考虑到尼达尼布的安全性和药代动力学特征已有充分记录，这一发现为重新利用尼达尼布作为新疗法来治疗对伊马替尼产生新耐药或获得性耐药的 GIST 患者提供了证据。耐药性仍然是胃肠道间质瘤（GIST）临床治疗的主要挑战。在这里，我们观察到尼达尼布可以克服由cKIT二次突变和FGF配体表达升高引起的伊马替尼耐药，从而为对伊马替尼产生耐药性的GIST患者提供新的潜在治疗方法。
Drug resistance remains a major challenge in the clinical treatment of gastrointestinal stromal tumours (GISTs). While acquired on‐target mutations of mast/stem cell growth factor receptor (KIT) kinase is the major resistance mechanism, activation of alternative signalling pathways may also play a role. Although several second‐ and third‐generation KIT kinase inhibitors have been developed that could overcome some of the KIT mutations conferring resistance, the low clinical responses and narrow safety window have limited their broad application. The present study revealed that nintedanib not only overcame resistance induced by a panel of KIT primary and secondary mutations, but also overcame ERK‐reactivation‐mediated resistance caused by the upregulation of fibroblast growth factor (FGF) activity. In preclinical models of GISTs, nintedanib significantly inhibited the proliferation of imatinib‐resistant cells, including GIST‐5R, GIST‐T1/T670I and GIST patient‐derived primary cells. In addition, it also exhibited dose‐dependent inhibition of ERK phosphorylation upon FGF ligand stimulation. In vivo antitumour activity was also observed in several xenograft GIST models. Considering the well‐documented safety and pharmacokinetic profiles of nintedanib, this finding provides evidence for the repurposing of nintedanib as a new therapy for the treatment of GIST patients with de novo or acquired resistance to imatinib. Drug resistance remains a major challenge in the clinical treatment of gastrointestinal stromal tumors (GISTs). Here, we observed that nintedanib can overcome imatinib resistance induced by cKIT secondary mutations and elevated FGF ligand expression, thus providing a new potential therapy for patients with GIST that acquired resistance to Imatinib.
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影响因子：
8.8
作者：
Joensuu H;Blay JY;Comandone A;Martin-Broto J;Fumagalli E;Grignani G;Del Muro XG;Adenis A;Valverde C;Pousa AL;Bouché O;Italiano A;Bauer S;Barone C;Weiss C;Crippa S;Camozzi M;Castellana R;Le Cesne A
通讯作者：
Le Cesne A
影响因子：
5.3
作者：
Lopes LF;Bacchi CE
通讯作者：
Bacchi CE
影响因子：
3.4
作者：
Kelly CM;Shoushtari AN;Qin LX;D'Angelo SP;Dickson MA;Gounder MM;Keohan ML;Mcfadyen C;Sjoberg A;Singer S;DeMatteo RP;Hwang S;Heinemann MH;Francis JH;Antonescu CR;Chi P;Tap WD
通讯作者：
Tap WD
DOI：
10.1073/pnas.0812413106
发表时间：
2009-02-03
影响因子：
11.1
作者：
Gajiwala, Ketan S.;Wu, Joe C.;Demetri, George D.
通讯作者：
Demetri, George D.
影响因子：
17.1
作者：
Banks, Erica;Grondine, Michael;Anjum, Rana
通讯作者：
Anjum, Rana