Raman, Renuka; Villefranc, Jacques A; Ullmann, Timothy M; Thiesmeyer, Jessica; Anelli, Viviana; Yao, Jun; Hurley, James R; Pauli, Chantal; Bareja, Rohan; Wha Eng, Kenneth; Dorsaint, Princesca; Wilkes, David C; Beg, Shaham; Kudman, Sarah; Shaw, Reid; Churchill, Michael; Ahmed, Adnan; Keefer, Laurel; Misner, Ian; Nichol, Donna; ... (2022). Inhibition of FGF receptor blocks adaptive resistance to RET inhibition in CCDC6-RET-rearranged thyroid cancer. Journal of experimental medicine, 219(6) Rockefeller University Press 10.1084/jem.20210390
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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.
Item Type: |
Journal Article (Original Article) |
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Division/Institute: |
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Präzisionsonkologie 04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Präzisionsonkologie |
UniBE Contributor: |
Rubin, Mark Andrew |
ISSN: |
1540-9538 |
Publisher: |
Rockefeller University Press |
Language: |
English |
Submitter: |
Pubmed Import |
Date Deposited: |
06 May 2022 09:14 |
Last Modified: |
05 Dec 2022 16:19 |
Publisher DOI: |
10.1084/jem.20210390 |
PubMed ID: |
35510953 |
BORIS DOI: |
10.48350/169770 |
URI: |
https://boris.unibe.ch/id/eprint/169770 |
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