Systems Biology Approaches for Identifying Synthetic Lethal Targets in Cancer
The development of therapeutic agent against cancer is based on targeting key signaling proteins that cancer highjacks and uses to survive. Although progress has been made to define cancer’s vulnerabilities, a subset of cancer drivers remain undruggable. To address this problem the field has attempted to identify drug targets that would selectively kill cancer cells and spare wild type tissue, a concept known as synthetic lethality. The work outlined here seeks to address major challenges in identifying synthetic lethal targets. First, I provide an overview of the platforms for synthetic lethal screening and highlight the advantages and caveats of each approach. Chapter three is focused on a case study where we developed a network-based integration method for published KRAS synthetic lethal studies and derived principles for synthetic lethal screening. The major findings of this study highlight principles of synthetic lethal screening and identify a subset of genes, which may offer new therapeutic targets in the context of oncogenic KRAS. Chapter four explores the use of PARP inhibitors in non-small cell lung cancer cell lines and derive molecular signatures associated with response and resistance to PARP inhibitor. Chapter 5 reports the results of a KRAS 4a/4b drug screen which highlight isoform specific vulnerabilities that may inform therapeutic strategies for KRAS mutant cancers.