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Published on: August 23, 2019
Inhibition of FGF receptor blocks adaptive resistance to RET inhibition in CCDC6-RET-rearranged thyroid cancer
Renuka Raman1, Jacques A Villefranc1, Timothy M Ullmann1
1Department of Surgery, Weill Cornell Medical College, New York, NY.
Abstract:
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.
Insights
Targeting RET (Rearranged during transfection) signaling is crucial for treating RET-rearranged cancers. Activating FGFR signaling drives adaptive resistance to RET inhibitors by reactivating ERK signaling, but combined FGFR and RET inhibition overcomes this resistance.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Genetic alterations in RET are implicated in thyroid and lung cancers, leading to ERK and AKT pathway activation.
- Selective RET inhibitors show efficacy in tumors with RET alterations, but resistance mechanisms require elucidation.
Purpose of the Study:
- To investigate adaptive resistance mechanisms to RET inhibitors in RET-rearranged thyroid cancer.
- To identify therapeutic strategies to overcome RET inhibitor resistance.
Main Methods:
- Comprehensive molecular and genomic analysis of a patient with RET-rearranged thyroid cancer.
- Drug screening, proteomic, and biochemical profiling.
- In vitro and in vivo (animal models) studies of CCDC6-RET-rearranged thyroid cancer.
Main Results:
- Adaptive resistance to RET inhibitors was identified, characterized by rapid ERK signaling reactivation.
- Fibroblast Growth Factor Receptor (FGFR) signaling activation was identified as a key mechanism driving this adaptive resistance.
- Combined inhibition of FGFR and RET prevented adaptive resistance, reduced cell viability, and decreased tumor growth.
Conclusions:
- FGFR signaling activation is a critical adaptive resistance mechanism to RET inhibitors in RET-rearranged thyroid cancer.
- Combined FGFR and RET inhibition represents a promising therapeutic strategy to overcome resistance and improve treatment outcomes.
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