PMCID string | Title string | Sentences string |
|---|---|---|
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | When the tumour size of xenografts reached ~ 2000 mm, biopsies were obtained and the mice were castrated. |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | The tumour growth inhibition (TGI) was calculated according to actual tumour weight using the formula: (W vehicle − W Test)/W Vehicle × 100% in which W is defined as actual tumour weight. |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | Standard procedures of immunohistochemistry staining have been described previously . |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | Briefly, tumour tissue samples were processed for paraffin embedding. |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | The sections were stained with haematoxylin and eosin (H&E), human Ki‐67 (ZSGB‐BIO, Beijing, China) and in situ Cell Death Detection Kit (POD; Roche, Mannheim, Germany), respectively. |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | We first tested the antiproliferative effects of nintedanib, sunitinib, imatinib, avapritinib and ripretinib against a panel of BaF3 cells transformed by KIT kinase; their proliferation depends on the KIT kinase (Fig. 1A, Table S1). |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | The results demonstrated that nintedanib displayed better potency than sunitinib or imatinib in KIT wt BaF3 cells (GI50 values were 0.058, 0.59 and 0.11 μm, respectively). |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | For primary mutations in the juxtamembrane domain, including L576P and V559D/G, nintedanib exhibited better activity than sunitinib, imatinib, avapritinib and ripretinib. |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | Nintedanib, sunitinib and ripretinib were highly effective in BaF3 cells with the KIT V654A mutation and the mixed V654A/V559D and T670I/V559D mutations, which are secondary imatinib‐resistant mutations in the ATP‐binding pocket. |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | Interestingly, for BaF3 cells with the imatinib‐resistant gatekeeper mutation T670I, nintedanib was more potent than sunitinib, avapritinib and ripretinib (GI50 < 0.0003 μm vs 0.005 μm; 0.039μm; 0.017μm). |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | In addition, nintedanib showed similar potencies to avapritinib and ripretinib, and the efficacy is better than sunitinib or imatinib in activating KIT loop mutations, such as D816H/V and D820E/G/Y. Overall, these results suggested that most of the secondary imatinib‐resistant mutations in the activation loop and ATP‐binding pocket of KIT are sensitive to nintedanib, especially the gatekeeper mutation T670I, compared with sunitinib and imatinib, avapritinib and ripretinib. |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | Nintedanib inhibits KIT wt and KIT mutant in vitro. ( |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | The heatmap shows GI50 values (growth inhibitory activity) of nintedanib, imatinib, sunitinib, avapritinib and ripretinib in BaF3 isogenic cell lines whose proliferation were depend on KIT wt and KIT mutant kinase. |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | The cell lines were treated with drugs (0–10 μm) for 3 days (n = 3, independent experiments). ( |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | The heatmap shows that EC50 (effective concentrations) values was calculated by quantifying the levels of KIT Y703/Y719/Y823 relative to KIT after a various dose of nintedanib treatment for 2 h. (C) Relativity between GI50s and EC50s on KIT wt and mutants of BaF3 isogenic cell lines panel. ( |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | Nintedanib inhibits KIT wt and KIT mutant proteins using ADP‐Glo biochemical assay. |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | Data are shown as mean ± SD (n = 2, independent experiments). |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | High GI50 (EC50) and low GI50 (EC50) values were corresponded by red colour and green colour, respectively. |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | To ensure that the antiproliferative effects of nintedanib in engineered BaF3 cells were due to mutations in on the KIT signalling pathway, we then examined its inhibitory effects on KIT Y703, Y719 and Y823 phosphorylation (Fig. 1B, Fig. S1 and Table S2). |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | Western blotting showed that nintedanib potently inhibited the autophosphorylation of KIT wt and KIT with V559A/D/G, L576P, T670I, D820E, Y823D or A829P mutations but was much less potent on the autophosphorylation of KIT with D816V and N822K mutations, which showed similar trends to the growth inhibition of the KIT BaF3 cells (Fig. 1C). |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | In addition, to test the inhibitory activity of nintedanib in cells with KIT wt and mutant proteins, we used an ADP‐Glo biochemical assay (Fig. 1D, Table S3). |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | The data revealed that nintedanib was potent against KIT wt (IC50 = 3.85 nm), KIT V654A (IC50 = 7.94 nm), KIT T670E (IC50 = 59.4 nm), KIT T670I (IC50 = 1.65 nm), KIT D816H and D816V (IC50 = 1.14 nm and 2.38 nm, respectively), KIT D820E (IC50 = 3.14 nm), KIT N822K (IC50 = 2.6 nm), KIT Y823D (IC50 = 3.5 nm), and KIT A829P (IC50 = 2.64 nm). |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | It was more potent against the mixed mutation T670I/V559D (IC50 < 0.5 nm) but relatively less potent against the KIT T670E mutation. |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | These data suggested that nintedanib can suppress the proliferation of a panel of BaF3 cells due to its inhibitory effect on primary and secondary KIT kinase mutations. |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | We next assessed the antiproliferative effects of nintedanib against a series of GIST cell lines and human primary GIST cells derived from three GIST patients expressing KIT wt, KIT‐V559D or KIT‐K642E mutations. |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | The study showed that compared with imatinib and sunitinib, nintedanib was more potent against GIST‐T1 cells (GI50 = 1.7 nm; Fig. 2A), which harbour the Δ560–578 mutation in the juxtamembrane region of KIT. |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | Nintedanib also showed potency similar to sunitinib against GIST882 cells, which harbours the primary K642E mutation in the KIT c‐helix, but it was more potent than imatinib. |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | In addition, nintedanib was more effective than sunitinib in the GIST‐T1‐T670I and GIST‐5R cell lines, which are both imatinib resistant and harbour gatekeeper T670I and Δ560–578 KIT mutations. |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | For GIST‐48B cells, which are KIT‐independent cells, none of the three compounds showed activity. |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | Similarly, in human primary GIST cells harbouring KIT wt and the KIT‐V559D and KIT‐K642E mutations, nintedanib displayed high potency in a dose‐dependent manner (Fig. 2B, Table S4). |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | Effects of nintedanib on human GIST cell lines and human primary GIST cells. ( |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | Antiproliferative effects of nintedanib against GIST‐T1, GIST‐882, GIST‐5R, GIST‐48B and GIST‐T1‐T670I cell lines. |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | The cell lines were treated with drugs (0–10 μm) for 3 days using CellTiter‐Glo assay. |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | Data are shown as mean ± SD (n = 3, independent experiments). ( |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | Anti‐proliferation of human primary GIST cells after treatment with nintedanib for 6 days using CellTiter‐Glo assay. |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | Data are shown as mean ± SD (n = 3, independent experiments). ( |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | Inhibition of signalling pathways of KIT in GIST‐T1, GIST‐882, GIST‐5R and GIST‐48B cell lines after treatment with nintedanib for 4 h (immunoblotting; n = 3, independent experiments). ( |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | Effects of nintedanib on cell cycle progression after treatment for 24–72 h (flow cytometry). |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | This experiment was carried out once. ( |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | Nintedanib induced GIST‐T1, GIST‐882, GIST‐5R and GIST‐48B cell line apoptosis. |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | This experiment was conducted once. |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | To further ensure on‐target efficacy in GIST cell lines, we tested the response of the KIT‐mediated signalling pathway upon nintedanib treatment (Fig. 2C). |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | Nintedanib potently inhibited the phosphorylation of KIT, such as Y703, Y719 and Y823, and downstream mediators, such as AKT and STAT3, which was also observed in cell lines with high expression RTK drug targets , in GIST‐T1 and GIST‐882 (imatinib sensitive) cells. |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | Interestingly, in GIST‐5R (imatinib resistant) cells, nintedanib was more potent than sunitinib against KIT Y719 phosphorylation, which regulates SCF‐mediated cell migration , and both nintedanib and sunitinib displayed profound inhibitory effects on KIT Y703 and Y823 phosphorylation. |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | As expected, in the GIST‐48B cell line, which is KIT independent, neither compound showed an effect on the downstream mediators of the KIT signalling pathway. |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | We then evaluated the effects of nintedanib on cell cycle progression. |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | The results showed that nintedanib induced cell cycle arrest in the G0‐G1 phase starting at 30 nm in GIST‐T1 and GIST‐882 (imatinib sensitive) and GIST‐5R (imatinib resistant) cells but not in GIST‐48B (KIT independent) cells (Fig. 2D). |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | Nintedanib induced the apoptosis of KIT‐mutant GIST cell lines but not the KIT‐independent GIST‐48B cell line (Fig. 2E). |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | Together, these data demonstrated that nintedanib suppressed proliferation and KIT pathway signalling in imatinib‐resistant cells harbouring a KIT‐dependent resistance mutation and preclinical GIST models in vitro. |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | GIST‐T1, KIT‐T670I/BaF3, GIST‐T1‐T670I and GIST‐5R mouse xenograft models were used to assess the in vivo antitumour efficacy of nintedanib. |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | At doses as high as 100 mg·kg·day, nintedanib caused no significant body weight changes in any treatment group. |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | In the GIST‐T1 mouse xenograft models, tumour growth was suppressed by nintedanib in a dose‐dependent manner, and the tumour growth inhibition (TGI) rate was 72.3% at the 50 mg·kg dose and 78.2% at the 100 mg·kg dose (Fig. 3A). |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | In the KIT‐T670I/BaF3‐ and GIST‐T1‐T670I‐inoculated mouse models, 100 mg·kg nintedanib nearly completely suppressed tumour growth, with TGI values of 93.3% and 80.3%, respectively, while imatinib showed a limited effect on tumour growth at the same doses (Fig. 3B,C). |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | As expected, nintedanib inhibited the KIT signalling pathway in KIT‐T670I/BaF3 tumour tissues in a dose‐dependent manner (Fig. S2). |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | In the GIST‐5R mouse xenograft models, tumour growth was inhibited by nintedanib in a dose‐dependent manner, and the TGI rate was 71.6% at 100 mg·kg, while imatinib had no effect on tumour growth (Fig. 3D). |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | Immunohistochemical (IHC) staining showed that nintedanib inhibited cell proliferation and induced cell apoptosis in the GIST‐T1 and GIST‐5R mouse xenograft models in a dose‐dependent manner (Figs S3 and S4). |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | These results confirmed that nintedanib elicited robust antitumour efficacy in KIT Δ560–578 and T670I mutation‐dependent tumour models at well‐tolerated doses. |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | In vivo antitumour efficacy of Nintedanib against GIST‐T1, KIT‐T670I/BaF3, GIST‐T1‐T670I and GIST‐5R mouse xenograft model. ( |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | Effects of nintedanib on GIST‐T1 mouse xenograft model (n = 3, independent experiments). ( |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | Effects of nintedanib on BaF3‐KIT‐T670I mouse allograft model (n = 5, independent experiments). ( |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | Effects of nintedanib on GIST‐T1‐T670I mouse xenograft model (n = 5, independent experiments). ( |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | Effects of nintedanib on GIST‐5R mouse xenograft model (n = 3, independent experiments). |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | Animals were treated orally once a day with a various of dose of the drugs. |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | Data are shown as mean ± SEM, n.s., |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | not significant; *P‐value < 0.05; **P‐value < 0.01; ****P < 0.0001 (one‐way ANOVA). |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | As previously reported , imatinib resistance in GISTs in which FGF2 is universally highly expressed can be induced by MAP kinase activation through FGF signalling. |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | Therefore, we next investigated whether FGFR‐mediated reactivation of the MAPK pathway can attenuate the antiproliferative effect of nintedanib in GISTs (Fig. 4A). |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | The results showed that nintedanib was more potent than imatinib and sunitinib against the GIST‐T1 and GIST‐882 cells with FGF signalling pathway activated by FGF2 ligand. |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | To address the molecular mechanism underlying the growth inhibition of the GIST‐T1 and GIST882 cell line by nintedanib in the presence of 20 ng·mL FGF2, we tested the activated states of downstream mediators of the KIT and FGF signalling pathways (Fig. 4B). |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | As expected, nintedanib strongly inhibited the KIT downstream signalling pathway and phospho‐FRS2α, the major downstream substrate of FGFRs. |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | By comparison, imatinib inhibited only the autophosphorylated KIT and downstream signalling pathways but not ERK, which was due to reactivated FGFR signalling. |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | To test whether nintedanib can overcome the resistance induced by imatinib, which enables FGFR signalling activation, we examined the effects of nintedanib on KIT and FGFR‐mediated signalling pathways after imatinib treatment (Fig. 4C). |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | The results demonstrated that nintedanib could strongly inhibit FGFR signalling. |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | Interestingly, the phosphorylation of histone 2A family member X (γ‐H2AX) , which is an indication for DNA injury, was remarkably increased in this experiment (Fig. S5). |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | We then tested the effects of nintedanib on human primary GIST cells that expressed the KIT‐V559D, KIT‐K642E and KIT‐wt in KIT (Fig. 4D). |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | The results showed that nintedanib could strongly inhibit the autophosphorylated KIT, phospho‐FRS2α and KIT downstream signalling pathways with 20 ng·mL FGF2. |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | In addition, nintedanib increased the phosphorylation of H2AX in the primary tumour cells derived from KIT‐V559D and KIT‐K642E GIST patients, which suggested that nintedanib could induce apoptosis in part through DNA double‐strand breaks (Fig. S6). |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | Anti‐proliferation of human GIST cancer cell lines and patient‐derived primary cells after treating with nintedanib and imatinib within FGF‐2. ( |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | Effects of nintedanib, imatinib and sunitinib on proliferation of GIST‐T1 and GIST‐882 cell lines within 20 ng·mL FGF2 for 3 days using CellTiter‐Glo assay. |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | Data are shown as mean ± SD (n = 3, independent experiments). ( |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | Effects of nintedanib and imatinib on the FGFR and KIT signalling pathways in GIST‐T1 and GIST‐882 cell lines within 20 ng·mL FGF2 for 4 h (immunoblotting; n = 3, independent experiments). ( |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | GIST‐T1 and GIST‐882 cell lines were treated with imatinib for 4 h to activate FGF/FGFR signalling pathway, after which imatinib was removed and the cells were treated with nintedanib for 4 h for immunoblotting analysis. |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | This experiment was conducted once. ( |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | Effects of nintedanib and imatinib on the FGFR and KIT signalling pathways in three GIST patients within 20 ng·mL FGF2 for 4 h (immunoblotting). |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | Considering a previous report showing that the effect of imatinib was reduced in a GIST882 xenograft model by inducing activation of FGFR signalling , we tested the antitumour efficacy of nintedanib on GIST882 tumour‐bearing mice. |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | A GIST882 xenograft model was treated with imatinib or nintedanib twice daily for 1 day and 4 days. |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | The phosphorylation of FRS2α was increased after treatment with imatinib for 4 days, a finding not found with nintedanib treatment and was consistent with the imatinib‐induced activation of the FGF signalling pathway (Fig. 5A). |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | We next determined whether nintedanib was more effective than imatinib in vivo. |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | In the GIST882 cell‐inoculated mouse xenograft model, nintedanib at doses as high as 100 mg·kg·day showed no apparent toxicity (Fig. 5B). |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | Tumour growth was inhibited by nintedanib in a dose‐dependent manner, and the TGI rate was 60.8% at 100 mg·kg·day, whereas imatinib showed a limited effect on tumour growth at the same dose. |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | After drug withdrawal, nintedanib displayed a long‐lasting response (Fig. 5C,D). |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | As expected, nintedanib, but not imatinib, reduced the phosphorylation of FRS2α, which is a downstream substrate of FGFR (Fig. 5E). |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | These results support the notion that the application of nintedanib may be a new strategy for enhancing the treatment for GIST patients with de novo or acquired resistance to imatinib. |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | Effect of Nintedanib and Imatinib in GIST‐882 mouse xenograft models in vivo. ( |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | Effects of nintedanib and Imatinib on the FGFR signalling pathways in GIST‐882 mouse xenograft models (control, n = 2, independent experiments; treated, n = 3, independent experiments). ( |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | B‐D) Effect of nintedanib and imatinib on GIST‐882 mouse xenograft models (n = 5, independent experiments). ( |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | Effects of nintedanib and imatinib on the FGFR signalling pathways in GIST‐882 mouse xenograft models after treated by 40 days (n = 3, independent experiments). |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | Animals were treated orally once a day with a various of dose of the drugs. |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | Data are shown as mean ± SEM, *P‐value < 0.05; **P‐value < 0.01; ***P‐value < 0.001 (one‐way ANOVA). |
PMC9019892 | Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours | Because of advancements in next‐generation sequencing technology, it has been found that secondary mutations of kinases are not the only mechanisms of drug resistance and that the activation of alternative pathways can also contribute to drug resistance. |
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