159 (PB039) - A combination vertical inhibition approach with inhibitors of SHP2 and ERK provides improved activity in KRAS-mutant pancreatic and colorectal cancer models

Abstract

Background: Inhibitors of the MAPK pathway are approved therapeutic agents with a high initial response rate, however single agent use of MAPK inhibitors in the clinic is often limited by resistance. Resistance commonly occurs through mechanisms which result in reactivation of MAPK signaling, such as activation of receptor tyrosine kinases (RTKs). Vertical pathway combination strategies are therefore of interest for addressing resistance through pathway reactivation. Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2) is a key regulator of the MAPK pathway downstream of RTKs and upstream of RAS, whilst ERK1/2 (ERK) is the final node of the kinase cascade.