Drosophila Cancer Models Identify Functional Differences between Ret Fusions.
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.
Department 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.
Sarah
S
Levinson
Department 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. Electronic address: ross.cagan@mssm.edu.
Ross L
RL
Cagan
D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000187:drug effects / Q000378:metabolism*; D004357:Drug Synergism; D058750:Epithelial-Mesenchymal Transition; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051096:Proto-Oncogene Proteins c-ret / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D051096:Proto-Oncogene Proteins c-ret