Pre-Conference Workshop Day
*Please be aware the venue for the Workshop day has changed*
Workshop A - Tuesday, September 17 (10:30 am - 13:00 pm)
Exploring Current Caveats and Future Challenges in Understanding Oncogenic RAS Structure and Function: Influence of the Mutations
Enabled by the latest technological advances, our understanding in RAS biology and its oncogenic properties has taken a giant leap in recent years. Still, our limited knowledge is hindering the ongoing efforts to develop RAS-targeting therapies. In this workshop we discuss to what extent we currently understand the oncoprotein and its behavior. Also, we will cover the important aspects that needs to be addressed to enable successful RAS-therapies in future.
Topics to be covered:
• What does the publicly available RAS structural data tell us and what does it not?
• Are oncogenic RAS mutations totally random events or are they context dependent (cell- and tissue-specific)?
• How similar are RAS missense mutants in different positions (e.g. pos. 12 vs. 61) and in the same position (e.g. G12D vs. G12V)?
• What is the influence of a mutation to RAS dynamics?
• What would be the optimal balance between promiscuous (all isoforms, wild-type) and a mutation specific (e.g. G12C) RAS-targeting?
Marie Skłodowska-Curie Fellow
University of Tübingen
Workshop B - Tuesday, September 17 (14.00pm - 16.30pm)
Empowering Anti-RAS Strategies: From Mouse Models to Clinical Research
KRAS is one of the most frequently mutated oncogenes in cancer and KRAS mutations are commonly associated with resistance to therapy and poor prognosis. Till very recently, KRAS was not directly druggable and modeling therapeutic strategies for KRAS mutant cancers were oriented towards the identification of susceptibilities in downstream signaling pathways. One unresolved aspect of KRAS biology with potential to translate in patient stratification criteria is the difference between distinct KRAS activating mutations in terms of downstream signaling, regulation and drug
sensitivity. KRAS dimerization/clusterization may play a critical role in generating these differences and this aspect is largely unstudied. Understanding the biochemical and biological differences among specific KRAS mutants and the properties of RAS dimerization is essential to discover new actionable vulnerabilities for mutant KRAS.
Topics to be covered:
• State of the art of KRAS-driven mouse models
• How can we improve the identification of biomarkers for better treatment options?
• Understanding the biological differences between specific mutant KRAS isoforms. What are meaningful measures of differences?
• How can genetic models help us define RAS mutationspecific differences in signal transduction pathways?
• What are weaknesses in widely used mouse models of KRAS-driven disease that may obscure identification of mutation-specific differences in vivo?
• How can genetic models allow us to differentiate between tumor initiating and tumor maintaining effects of RAS.
• How can genetic models be used to predict the toxicity of new RAS-directed strategies?
Dana-Farber Cancer Institute
UT Southwestern Medical Center