Patients with Multiple Endocrine Neoplasia Type 2 and Familial Medullary Thyroid Carcinoma have activating mutations of the Ret proto-oncogene. In this transgenic model, mutated Drosophila Ret is targeted to the developing eye, resulting in a rough, aberrant eye. This appearance results from aberrant cell proliferation, inappropriate cell fate specification, and excessive Ras pathway activation. Genetic analyses have shown that mutated dRet acts through the Ras-ERK, Src and Jun kinase pathways; therefore, this model allows screening of multiple proteins and pathways required for the phenotype.

Proof of concept that a compound that reverses the eye phenotype is also active in humans is provided by an academic experiment conducted by one of the Founders. ZD6474 is a small molecule inhibitor of the vascular endothelial growth factor receptor 2 kinase, epithelial growth factor receptor kinase and Ret kinase. Feeding ZD6474 to Drosophila expressing mutant dRet prevented tumor formation, providing an important in vivo validation of this compound for cancer. ZD6474 is currently in phase 3 clinical trials for medullary thyroid cancer, and has entered trials for non-small cell lung cancer and and other indications.

Targeting oncogenic Ret to the developing Drosophila eye led to a ‘rough eye’ phenotype with many aspects that are reminiscent of tumorigenesis. From Vidal et al, 2006.