Inhibition of FGF receptor blocks adaptive resistance to RET inhibition in CCDC6-RET-rearranged thyroid cancer.
Journal
The Journal of experimental medicine
ISSN: 1540-9538
Titre abrégé: J Exp Med
Pays: United States
ID NLM: 2985109R
Informations de publication
Date de publication:
06 06 2022
06 06 2022
Historique:
received:
16
02
2021
revised:
23
11
2021
accepted:
18
03
2022
entrez:
5
5
2022
pubmed:
6
5
2022
medline:
10
5
2022
Statut:
ppublish
Résumé
Genetic alterations in RET lead to activation of ERK and AKT signaling and are associated with hereditary and sporadic thyroid cancer and lung cancer. Highly selective RET inhibitors have recently entered clinical use after demonstrating efficacy in treating patients with diverse tumor types harboring RET gene rearrangements or activating mutations. In order to understand resistance mechanisms arising after treatment with RET inhibitors, we performed a comprehensive molecular and genomic analysis of a patient with RET-rearranged thyroid cancer. Using a combination of drug screening and proteomic and biochemical profiling, we identified an adaptive resistance to RET inhibitors that reactivates ERK signaling within hours of drug exposure. We found that activation of FGFR signaling is a mechanism of adaptive resistance to RET inhibitors that activates ERK signaling. Combined inhibition of FGFR and RET prevented the development of adaptive resistance to RET inhibitors, reduced cell viability, and decreased tumor growth in cellular and animal models of CCDC6-RET-rearranged thyroid cancer.
Identifiants
pubmed: 35510953
pii: 213197
doi: 10.1084/jem.20210390
pmc: PMC9082625
pii:
doi:
Substances chimiques
CCDC6 protein, human
0
Cytoskeletal Proteins
0
Receptors, Fibroblast Growth Factor
0
Proto-Oncogene Proteins c-ret
EC 2.7.10.1
RET protein, human
EC 2.7.10.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Weill Cornell Medical College
Organisme : Functional Genomics Initiative
Organisme : Memorial Sloan Kettering Cancer Institute
Organisme : International Thyroid Oncology Group
Informations de copyright
© 2022 Raman et al.
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