Complementary activity of tyrosine kinase inhibitors against secondary kit mutations in imatinib-resistant gastrointestinal stromal tumours

Br J Cancer. 2019 Mar;120(6):612-620. doi: 10.1038/s41416-019-0389-6. Epub 2019 Feb 22.


Background: Most patients with KIT-mutant gastrointestinal stromal tumours (GISTs) benefit from imatinib, but treatment resistance results from outgrowth of heterogeneous subclones with KIT secondary mutations. Once resistance emerges, targeting KIT with tyrosine kinase inhibitors (TKIs) sunitinib and regorafenib provides clinical benefit, albeit of limited duration.

Methods: We systematically explored GIST resistance mechanisms to KIT-inhibitor TKIs that are either approved or under investigation in clinical trials: the studies draw upon GIST models and clinical trial correlative science. We subsequently modelled in vitro a rapid TKI alternation approach against subclonal heterogeneity.

Results: Each of the KIT-inhibitor TKIs targets effectively only a subset of KIT secondary mutations in GIST. Regorafenib and sunitinib have complementary activity in that regorafenib primarily inhibits imatinib-resistance mutations in the activation loop, whereas sunitinib inhibits imatinib-resistance mutations in the ATP-binding pocket. We find that rapid alternation of sunitinib and regorafenib suppresses growth of polyclonal imatinib-resistant GIST more effectively than either agent as monotherapy.

Conclusions: Our data highlight that heterogeneity of KIT secondary mutations is the main mechanism of tumour progression to KIT inhibitors in imatinib-resistant GIST patients. Therapeutic combinations of TKIs with complementary activity against resistant mutations may be useful to suppress growth of polyclonal imatinib-resistance in GIST.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • CHO Cells
  • Clinical Trials, Phase II as Topic
  • Cricetulus
  • Drug Resistance, Neoplasm
  • Female
  • Gastrointestinal Neoplasms / drug therapy*
  • Gastrointestinal Neoplasms / enzymology
  • Gastrointestinal Neoplasms / genetics
  • Gastrointestinal Stromal Tumors / drug therapy*
  • Gastrointestinal Stromal Tumors / enzymology
  • Gastrointestinal Stromal Tumors / genetics
  • Humans
  • Imatinib Mesylate / pharmacology
  • Mice
  • Mice, Nude
  • Mutation*
  • Phenylurea Compounds / pharmacology
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-kit / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-kit / genetics
  • Proto-Oncogene Proteins c-kit / metabolism
  • Pyridines / pharmacology
  • Sunitinib / pharmacology
  • Xenograft Model Antitumor Assays


  • Phenylurea Compounds
  • Protein Kinase Inhibitors
  • Pyridines
  • regorafenib
  • Imatinib Mesylate
  • KIT protein, human
  • Proto-Oncogene Proteins c-kit
  • Sunitinib