Systems Biology Approaches for Identifying Synthetic Lethal Targets in Cancer
- Author(s): Ku, Angel Alejandro
- Advisor(s): Bandyopadhyay, Sourav
- et al.
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.