Unbiased Combinatorial Genomic Approaches to Identify Alternative Therapeutic Targets within the TSC Signaling Network
Final rept. 1 Jun 2012-31 May 2015
HARVARD UNIV BOSTON MA
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The goal of this project was to identify robust synthetic lethal interactions between TSC and kinases and phosphatases by taking advantage of the evolutionary conservation of the pathway. We first identified such interactions in Drosophila cells and tested the candidates in TSC human patient cells. We identified three hits mRNA-Cap, Pitslre and CycT that scored as synthetic lethal with both TSC1 and TSC2 mutations in Drosophila and validated the mammalian orthologs of the three hits as having synthetic lethal relationships with TSC2 in both mouse and human cells, as their depletion selectively decreases the viability of TSC2 null cells. These candidates are now strong drug candidates for TSC.
- Anatomy and Physiology
- Medicine and Medical Research