The evolution of RET inhibitor resistance in RET-driven lung and thyroid cancers Journal Article


Authors: Rosen, E. Y.; Won, H. H.; Zheng, Y.; Cocco, E.; Selcuklu, D.; Gong, Y.; Friedman, N. D.; de Bruijn, I.; Sumer, O.; Bielski, C. M.; Savin, C.; Bourque, C.; Falcon, C.; Clarke, N.; Jing, X.; Meng, F.; Zimel, C.; Shifman, S.; Kittane, S.; Wu, F.; Ladanyi, M.; Ebata, K.; Kherani, J.; Brandhuber, B. J.; Fagin, J.; Sherman, E. J.; Rekhtman, N.; Berger, M. F.; Scaltriti, M.; Hyman, D. M.; Taylor, B. S.; Drilon, A.
Article Title: The evolution of RET inhibitor resistance in RET-driven lung and thyroid cancers
Abstract: The efficacy of the highly selective RET inhibitor selpercatinib is now established in RET-driven cancers, and we sought to characterize the molecular determinants of response and resistance. We find that the pre-treatment genomic landscape does not shape the variability of treatment response except for rare instances of RAS-mediated primary resistance. By contrast, acquired selpercatinib resistance is driven by MAPK pathway reactivation by one of two distinct routes. In some patients, on- and off-target pathway reactivation via secondary RET solvent front mutations or MET amplifications are evident. In other patients, rare RET-wildtype tumor cell populations driven by an alternative mitogenic driver are selected for by treatment. Multiple distinct mechanisms are often observed in the same patient, suggesting polyclonal resistance may be common. Consequently, sequential RET-directed therapy may require combination treatment with inhibitors targeting alternative MAPK effectors, emphasizing the need for prospective characterization of selpercatinib-treated tumors at the time of monotherapy progression. © 2022, The Author(s).
Journal Title: Nature Communications
Volume: 13
ISSN: 2041-1723
Publisher: Nature Publishing Group  
Date Published: 2022-03-18
Start Page: 1450
Language: English
DOI: 10.1038/s41467-022-28848-x
PUBMED: 35304457
PROVIDER: scopus
PMCID: PMC8933489
DOI/URL:
Notes: Article -- Export Date: 1 April 2022 -- Source: Scopus -- Erratum published and be accessed at 10.1038/s41467-022-29700-y
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MSK Authors
  1. James A Fagin
    168 Fagin
  2. Natasha Rekhtman
    391 Rekhtman
  3. Eric J Sherman
    303 Sherman
  4. Marc Ladanyi
    1277 Ladanyi
  5. David Hyman
    352 Hyman
  6. Xiaohong Jing
    21 Jing
  7. Michael Forman Berger
    701 Berger
  8. Alexander Edward Drilon
    552 Drilon
  9. Barry Stephen Taylor
    236 Taylor
  10. Helen Hyeong-Eun Won
    109 Won
  11. Maurizio Scaltriti
    169 Scaltriti
  12. Selcuk Onur Sumer
    32 Sumer
  13. Fanli   Meng
    24 Meng
  14. Emiliano Cocco
    31 Cocco
  15. Craig Bielski
    23 Bielski
  16. Sophie Shifman
    10 Shifman
  17. Youyun Zheng
    10 Zheng
  18. Ezra Y Rosen
    38 Rosen
  19. Yixiao Gong
    6 Gong
  20. Catherine Zimel
    6 Zimel
  21. Fan Wu
    16 Wu
  22. Christina Jade Falcon
    36 Falcon
  23. Casey Savin
    4 Savin
  24. Nikeysha Clarke
    1 Clarke