NTRK kinase domain mutations in cancer variably impact sensitivity to type I and type II inhibitors

Romel Somwar, Nicolle E. Hofmann, Bryan Smith, Igor Odintsov, Morana Vojnic, Irina Linkov, Ashley Tam, Inna Khodos, Marissa S. Mattar, Elisa de Stanchina, Daniel Flynn, Marc Ladanyi, Alexander Drilon, Ujwal Shinde, Monika A. Davare

Research output: Contribution to journalArticlepeer-review

Abstract

Tyrosine kinase domains dynamically fluctuate between two main structural forms that are referred to as type I (DFG-in) or type II (DFG-out) conformations. Comprehensive data comparing type I and type II inhibitors are currently lacking for NTRK fusion-driven cancers. Here we used a type II NTRK inhibitor, altiratinib, as a model compound to investigate its inhibitory potential for larotrectinib (type I inhibitor)-resistant mutations in NTRK. Our study shows that a subset of larotrectinib-resistant NTRK1 mutations (V573M, F589L and G667C) retains sensitivity to altiratinib, while the NTRK1V573M and xDFG motif NTRK1G667C mutations are highly sensitive to type II inhibitors, including altiratinib, cabozantinib and foretinib. Moreover, molecular modeling suggests that the introduction of a sulfur moiety in the binding pocket, via methionine or cysteine substitutions, specifically renders the mutant kinase hypersensitive to type II inhibitors. Future precision treatment strategies may benefit from selective targeting of these kinase mutants based on our findings.

Original languageEnglish (US)
Article number776
JournalCommunications Biology
Volume3
Issue number1
DOIs
StatePublished - Dec 2020

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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