TRK XDFG mutations trigger a sensitivity switch from type I to II kinase inhibitors Journal Article


Authors: Cocco, E.; Lee, J. E.; Kannan, S.; Schram, A. M.; Won, H. H.; Shifman, S.; Kulick, A.; Baldino, L.; Toska, E.; Arruabarrena-Aristorena, A.; Kittane, S.; Wu, F.; Cai, Y.; Arena, S.; Mussolin, B.; Kannan, R.; Vasan, N.; Gorelick, A. N.; Berger, M. F.; Novoplansky, O.; Jagadeeshan, S.; Liao, Y.; Rix, U.; Misale, S.; Taylor, B. S.; Bardelli, A.; Hechtman, J. F.; Hyman, D. M.; Elkabets, M.; de Stanchina, E.; Verma, C. S.; Ventura, A.; Drilon, A.; Scaltriti, M.
Article Title: TRK XDFG mutations trigger a sensitivity switch from type I to II kinase inhibitors
Abstract: On-target resistance to next-generation TRK inhibitors in TRK fusion–positive cancers is largely uncharacterized. In patients with these tumors, we found that TRK xDFG mutations confer resistance to type I next-generation TRK inhibitors designed to maintain potency against several kinase domain mutations. Computational modeling and biochemical assays showed that TRKAG667 and TRKCG696 xDFG substitutions reduce drug binding by generating steric hin-drance. Concurrently, these mutations stabilize the inactive (DFG-out) conformations of the kinases, thus sensitizing these kinases to type II TRK inhibitors. Consistently, type II inhibitors impede the growth and TRK-mediated signaling of xDFG-mutant isogenic and patient-derived models. Collectively, these data demonstrate that adaptive conformational resistance can be abrogated by shifting kinase engagement modes. Given the prior identification of paralogous xDFG resistance mutations in other oncogene-addicted cancers, these findings provide insights into rational type II drug design by leverag-ing inhibitor class affinity switching to address recalcitrant resistant alterations. SIGNIFICANCE: In TRK fusion–positive cancers, TRK xDFG substitutions represent a shared liability for type I TRK inhibitors. In contrast, they represent a potential biomarker of type II TRK inhibitor activity. As all currently available type II agents are multikinase inhibitors, rational drug design should focus on selective type II inhibitor creation. © 2020 American Association for Cancer Research.
Journal Title: Cancer Discovery
Volume: 11
Issue: 1
ISSN: 2159-8274
Publisher: American Association for Cancer Research  
Date Published: 2021-01-01
Start Page: 126
End Page: 141
Language: English
DOI: 10.1158/2159-8290.Cd-20-0571
PROVIDER: scopus
PUBMED: 33004339
PMCID: PMC8012405
DOI/URL:
Notes: Article -- Export Date: 1 March 2021 -- Source: Scopus
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MSK Authors
  1. David Hyman
    347 Hyman
  2. Andrea Ventura
    48 Ventura
  3. Michael Forman Berger
    583 Berger
  4. Alexander Edward Drilon
    388 Drilon
  5. Barry Stephen Taylor
    227 Taylor
  6. Alison Michele Schram
    74 Schram
  7. Helen Hyeong-Eun Won
    103 Won
  8. Maurizio Scaltriti
    161 Scaltriti
  9. Jaclyn Frances Hechtman
    198 Hechtman
  10. Eneda   Toska
    30 Toska
  11. Ram   Kannan
    7 Kannan
  12. Emiliano Cocco
    28 Cocco
  13. Amanda Kulick
    15 Kulick
  14. Neil Vasan
    19 Vasan
  15. Sandra Misale
    10 Misale
  16. Yanyan Cai
    12 Cai
  17. Ji Eun Lee
    3 Lee
  18. Fan Wu
    6 Wu