Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib-induced KIT mutations in gastrointestinal stromal tumours.
Juan LiuJingjing GaoAoli WangZongru JiangShuang QiZiping QiFeiyang LiuKailin YuJiangyan CaoCheng ChenChen HuHong WuLi WangWenchao WangQing-Song LiuJing LiuPublished in: Molecular oncology (2022)
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.
Keyphrases
- idiopathic pulmonary fibrosis
- signaling pathway
- induced apoptosis
- growth factor
- stem cells
- interstitial lung disease
- cell proliferation
- cell cycle arrest
- chronic myeloid leukemia
- rheumatoid arthritis
- endoplasmic reticulum stress
- tyrosine kinase
- protein kinase
- endothelial cells
- diabetic rats
- high glucose
- single cell
- drug induced