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Drosophila Cancer Models Identify Functional Differences between Ret Fusions
Sarah Levinson1, Ross L Cagan1
1Department of Developmental and Regenerative Biology and Graduate School of Biomedical Sciences, Icahn School of Medicine at Mount Sinai, One Gustave Levy Place, New York, NY 10029-1020, USA.
Abstract:
We generated and compared Drosophila models of RET fusions CCDC6-RET and NCOA4-RET. Both RET fusions directed cells to migrate, delaminate, and undergo EMT, and both resulted in lethality when broadly expressed. In all phenotypes examined, NCOA4-RET was more severe than CCDC6-RET, mirroring their effects on patients. A functional screen against the Drosophila kinome and a library of cancer drugs found that CCDC6-RET and NCOA4-RET acted through different signaling networks and displayed distinct drug sensitivities. Combining data from the kinome and drug screens identified the WEE1 inhibitor AZD1775 plus the multi-kinase inhibitor sorafenib as a synergistic drug combination that is specific for NCOA4-RET. Our work emphasizes the importance of identifying and tailoring a patient's treatment to their specific RET fusion isoform and identifies a multi-targeted therapy that may prove effective against tumors containing the NCOA4-RET fusion.
Insights
Comparing RET fusions CCDC6-RET and NCOA4-RET in Drosophila revealed distinct signaling and drug sensitivities. NCOA4-RET is more severe, suggesting tailored therapies for specific RET fusion isoforms are crucial.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- RET fusions are oncogenic drivers in various cancers.
- CCDC6-RET and NCOA4-RET are two common RET fusion isoforms.
- Understanding isoform-specific mechanisms is vital for targeted therapy.
Purpose of the Study:
- To generate and compare Drosophila melanogaster models for CCDC6-RET and NCOA4-RET.
- To investigate the differential signaling networks and drug sensitivities of these RET fusions.
- To identify potential synergistic drug combinations for NCOA4-RET driven tumors.
Main Methods:
- Generation of Drosophila models for CCDC6-RET and NCOA4-RET.
- Phenotypic analysis including cell migration, delamination, and epithelial-mesenchymal transition (EMT).
- Functional screening of the Drosophila kinome and a cancer drug library.
Main Results:
- Both CCDC6-RET and NCOA4-RET induced migration, delamination, EMT, and lethality in Drosophila.
- NCOA4-RET exhibited more severe phenotypes than CCDC6-RET, mirroring clinical observations.
- Distinct signaling pathways and drug sensitivities were identified for each fusion.
- A synergistic combination of WEE1 inhibitor AZD1775 and sorafenib was identified specifically for NCOA4-RET.
Conclusions:
- RET fusion isoforms have distinct biological activities and therapeutic vulnerabilities.
- Isoform-specific modeling in Drosophila is a powerful tool for understanding RET-driven oncogenesis.
- A combination therapy of AZD1775 and sorafenib shows promise for NCOA4-RET-positive tumors.
