Drug resistance profiles of mutations in the RET kinase domain

Br J Pharmacol. 2018 Sep;175(17):3504-3515. doi: 10.1111/bph.14395. Epub 2018 Jul 19.


Background and purpose: Alterations in the tyrosine kinase enzyme RET are found in thyroid and lung cancer. While RET TK inhibitors (TKIs) are used to treat thyroid cancer and are in clinical trials for RET fusion-positive non-small cell lung cancer, the impact of mutations in the RET kinase domain on drug sensitivity is largely uncharacterized.

Experimental approach: We identified and analysed mutations in the RET kinase domain that conferred resistance to the TKIs cabozantinib, lenvatinib, vandetanib and nintedanib using RET kinase-dependent BaF3/KIF5B-RET (BaF3/KR) cells. We also examined the sensitivity of RET (M918T), a RET mutation prevalent in aggressive multiple endocrine neoplasia type 2B, to these TKIs in the context of BaF3/KR cells.

Key results: Fourteen mutations were analysed. Pan resistance to the four TKIs was found in six RET kinase domain mutations (L730I, V738A, V804L/M, Y806N, G810S). Seven RET kinase domain mutations (L730V, E732K, A807V, G810A, V871I, M918T, F998V) displayed selective resistance to one or more of these drugs. L730I/V and G810A/S had different drug resistance profiles. V871I, M918T and F998V mutations are located at distant sites away from the TKI binding pocket.

Conclusions and implications: A panel of TKI-resistant RET mutations were identified, and their drug sensitivities were cross-profiled. The results provide a reference for selecting appropriate TKIs to inhibit RET kinase domain mutants. Besides changes in the drug-interacting residues, mutations at distant sites could exert long-range effects resulting in TKI resistance. Among the four TKIs analysed here, nintedanib remained unaffected by mutations at the three distant sites.

Publication types

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

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Drug Resistance / genetics*
  • Humans
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / genetics
  • Mutation*
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins c-ret / genetics*
  • Thyroid Neoplasms / drug therapy
  • Thyroid Neoplasms / genetics


  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-ret
  • RET protein, human