Drosophila Cancer Models Identify Functional Differences between Ret Fusions

• Published in: Cell reports (Cambridge) 2016-09, Vol.16 (11), p.3052-3061
• Main Authors: Levinson, Sarah, Cagan, Ross L.
• Format: Article
• Language: English
• Subjects: Animals; Cell Movement - drug effects; Disease Models, Animal; Drosophila melanogaster - drug effects; Drosophila melanogaster - metabolism; Drug Synergism; Epithelial-Mesenchymal Transition; Neoplasms - metabolism; Neoplasms - pathology; Oncogene Proteins, Fusion - metabolism; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-ret - metabolism; Up-Regulation - drug effects
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.08.019

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. [Display omitted] •Drosophila RET fusion cancer models have multiple transformation phenotypes•Similar to patients, NCOA4-RET presents with more severe phenotypes than CCDC6-RET•CCDC6-RET and NCOA4-RET activate distinct pathways and have different drug sensitivity•A drug treatment, sorafenib plus AZD1775 (MK-1775), was effective for NCOA4-RET animals Levinson and Cagan examine two Drosophila RET-fusion models. They find that the N terminus contributes to the overall function of fusion proteins, including their response to therapeutics. Genetic and chemical genetic screens identify a drug combination of sorafenib plus AZD1775 as being effective against the NCOA4-RET fusion.