HIGH-THROUGHPUT IN VIVO DRUG SCREENING IN A CANCER PARADIGM

VILLEGAS SN; GUTIERREZ PEREZ I; GARCIA CASTILLO J; DA ROS VG; VALLEJO D; MIHÁLY J; DOMINGUEZ M

Barcelona

Conferencia; 23rd EUROPEAN DROSOPHILA RESEARCH CONFERENCE; 2013

The development of in vivo models suitable for small molecules screenings is an imperative move towards the discovery ofeffective pharmacological therapies for diseases, such as cancer. Here, we exploited a tumour-inducing paradigm in Drosophilamelanogaster to run a high-throughput drug screening and explore the effect of these compounds in tumorigenesis. Our modelentails the simultaneous over-activation of both Notch and Akt signalling pathways in the developing fly eye. The synchronizedhyperactivation of these two signals, that generates massive eye tumours, is also present in ~50% of human T-cellslymphoblastic leukaemia (T-ALL). Briefly, we have taken advantage of the GAL4-UAS system to drive the over-expression of bothAkt and the Notch receptor Delta from the eyeless promoter in developing larvae. L1 larvae were exposed to standardized drugdoses included in the food, and eye tumours incidence was scored in the adults. As result, we were able to identify a number ofdrugs that either attenuate or enhance tumorigenesis. Further analysis of the targets for significant drugs led us to identifyspecific cellular pathways that operate alongside Notch/Akt activation in controlling tumour progression. Subsequently, we usedRNA interference to knockdown relevant genes to mimic the effect of the selected drugs in a tissue-specific manner, leading us touncover new epistatic relationships with a potential role in tumorigenesis. These results support the idea that Drosophilascreening models are useful for in vivo drug discovery and to understand multifactorial hassle associated with tumour evolutionthat is otherwise difficult to be addressed ex vivo.