Inhibition of FGF receptor blocks adaptive resistance to RET inhibition in CCDC6-RET-rearranged thyroid cancer.

TitleInhibition of FGF receptor blocks adaptive resistance to RET inhibition in CCDC6-RET-rearranged thyroid cancer.
Publication TypeJournal Article
Year of Publication2022
AuthorsRaman R, Villefranc JA, Ullmann TM, Thiesmeyer J, Anelli V, Yao J, Hurley JR, Pauli C, Bareja R, Eng KWha, Dorsaint P, Wilkes DC, Beg S, Kudman S, Shaw R, Churchill M, Ahmed A, Keefer L, Misner I, Nichol D, Gumpeni N, Scognamiglio T, Rubin MA, Grandori C, Solomon JPatrick, Song W, Mosquera JMiguel, Dephoure N, Sboner A, Elemento O, Houvras Y
JournalJ Exp Med
Date Published2022 Jun 06
KeywordsAnimals, Cytoskeletal Proteins, Humans, Lung Neoplasms, Proteomics, Proto-Oncogene Proteins c-ret, Receptors, Fibroblast Growth Factor, Thyroid Neoplasms

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.

Alternate JournalJ Exp Med
PubMed ID35510953
PubMed Central IDPMC9082625
Grant ListR21 CA202540 / CA / NCI NIH HHS / United States
Related Faculty: 
James Solomon, M.D., Ph.D. Andrea Sboner, Ph.D. Juan Miguel Mosquera, M.D. Theresa Scognamiglio, M.D.

Pathology & Laboratory Medicine 1300 York Avenue New York, NY 10065 Phone: (212) 746-6464
Surgical Pathology: (212) 746-2700