Activating negative regulators of KRAS signaling as a novel anticancer paradigm

The KRAS pathway is the most frequently activated signaling node in human cancer. Even though targeting oncogenic RAS signaling elicits promising clinical responses, the effectiveness is often short-lived, as tumors develop resistance. We hypothesize that the rational modulation of feedback loops by combining oncogene inhibitors and tumor suppressor activators will majorly advance the attempts to target KRAS-driven tumors. Here, we plan to investigate the structural mechanisms of negative regulation of RAS signaling by protein phosphatase 2A (PP2A) and the LZTR1/CUL3 ubiquitin ligase complex, and use these targets towards developing novel small-molecule anticancer drugs. Although targeting these enzyme classes has remained challenging, we will employ structural biology and novel rational drug design approaches to identify and/or further optimize LZTR1 and PP2A activating drugs, followed by biochemical, cellular and in vivo assays for their validation.

Keywords:RAS pathway, rational drug design, cell signalling, cancer therapy, tumor suppressors

Disciplines:Cancer therapy, Structural biology, Cell signalling, Medicinal chemistry