Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib-induced KIT mutations in gastrointestinal stromal tumours

Mol Oncol. 2022 Apr;16(8):1761-1774. doi: 10.1002/1878-0261.13199. Epub 2022 Mar 6.


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.

Keywords: FGFR; GISTs; KIT; imatinib resistance; nintedanib.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents* / pharmacology
  • Antineoplastic Agents* / therapeutic use
  • Drug Resistance, Neoplasm / genetics
  • Gastrointestinal Stromal Tumors* / drug therapy
  • Gastrointestinal Stromal Tumors* / genetics
  • Gastrointestinal Stromal Tumors* / pathology
  • Humans
  • Imatinib Mesylate / pharmacology
  • Imatinib Mesylate / therapeutic use
  • Indoles
  • Mutation / genetics
  • Proto-Oncogene Proteins c-kit / genetics
  • Proto-Oncogene Proteins c-kit / metabolism
  • Pyrimidines / pharmacology
  • Up-Regulation / genetics


  • Antineoplastic Agents
  • Indoles
  • Pyrimidines
  • Imatinib Mesylate
  • Proto-Oncogene Proteins c-kit
  • nintedanib