Using Drosophila Models to Dissect Biology and Signaling Mechanisms in Rare Drug Resistant Variants of Lung Cancer
Authors: Sereene Kurzum 1; William Marsiglia 2; Chana Werther-Hecht 1; Bruce Gelb 1; Arvin Dar 2; Tirtha Das 1,3
Affiliations: 1) The Mindich Child Health and Development Institute, Dept. of Pediatrics, Department of Genetics and Genomic Science, Icahn School of Medicine at Mount Sinai; 2) Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai; 3) Dept. of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York NY USA
Keywords: h. tumorigenesis; i. receptor tyrosine kinase/phosphatase
Animal models and clinical data have vastly improved our understanding of gene variants that lead to human disease. In low occurrence cancers, rare gene variants arise in tumors of patients receiving targeted therapy. We had previously developed a Drosophila model for a rare lung cancer arising from a fusion oncogene KIF5B-RET and showed that this fusion protein assembles a complex signaling hub composed of multiple receptor tyrosine kinases (RTK’s). Our finding predicted that drugs designed to inhibit the RET-kinase activity alone may be insufficient to fully suppress oncogenic signaling from this hub. Subsequently, multiple clinical trials have shown poor response of RET-inhibitor drug treatment in patients harboring KIF5B-RET fusions in their lung tumors. Recently a few drugs, like loxo-292, designed to specifically and potently inhibit RET-kinase have been developed. In our fly model, treatment of KIF5B-RET with loxo-292 prevented phosphorylation of RET and some components of the hub like EGFR, but not other components like FGFR. This result indicates a potential mechanism of how drug resistant compensatory pathways could arise even after treatment with RET-kinase selective inhibitors. Moreover, recent clinical studies have shown that KIF5B-RET positive lung cancer patients develop rare KIF5B-RET-variants while undergoing treatment with RET-kinase selective drugs, and that these drug resistant variants reduce efficacy of the treatment. We developed one such model, using the human KIF5B-RETG810R, and found that this variant enhanced RET-kinase domain phosphorylation and enhanced activation of various RTK dependent pathways of the KIF5B-RET hub. Indeed, none of the studied RTK pathways were suppressed when KIF5B-RETG810R fly tissues were treated with loxo-292. In summary, our current findings using Drosophila models indicate that RET-selective drugs like loxo-292 may not fully suppress signaling of KIF5B-RET or KIF5B-RETG810R variant. Our ongoing studies predict potential molecular mechanisms of drug resistance to RET-selective inhibitors in various cancers and highlight the value of combining whole animal Drosophila models with chemical genetics to study human disease.