A Drosophila Approach to Ras Pathway Disease

Susumu Hirabayashi, Erdem Bangi, Tirtha Das, Benjamin Levine, Justin Graves, Alex Teague, Dhandapany Perundurai, Bruce Gelb, and Ross Cagan
Mount Sinai School of Medicine

The Ras pathway is involved in a broad palate of diseases. Typically, it acts in conjunction with other pathways; this cross-talk occurs at multiple levels: signaling, cell, tissue, and organism. Failure to account for these complexities has led to limited success in therapeutics that target Ras pathway activity. We have utilizedDrosophila to develop whole animal models designed to account for aspects of this complexity. I will discuss how our efforts highlight emergent properties as Ras signaling combines with other pathways in disease states such as cancers of the thyroid, breast, lung, and colon. We have developed these complex models both to explore emergent properties and as a whole animal screen for therapeutic compounds that attack multiple targets. Our drug surveys emphasize the importance of accounting for these multiple properties: drugs that attack Ras pathway alone work poorly in more complex models. Recently, we have collaborated with the Gelb laboratory to explore their model of Rasopathies including Noonan Syndrome. I will discuss our evidence that whole animal screening of even single mutation disease can benefit from therapeutics that address multiple targets.