An in Vivo shRNA-Drug Screen to Identify Novel Targeted Therapy Combinations for KRAS Mutant Cancers

: KRAS mutations occur in 90% of all pancreatic cancers and in 20% of all human cancers, but no effective therapies targeting KRAS have been developed. We proposed a functional genomic screen to identify gene targets that, when inhibited, cooperate with MEK inhibitors (which block signaling through the MAPK pathway, a key KRAS effector) to kill KRAS mutant pancreatic cancer cells in order to develop novel therapeutic combinations for these cancers. Our efforts identified several components within the MAPK pathway that can lead to feedback reactivation of MAPK signaling despite the presence of MEK inhibitors, creating a key vulnerability of MEK inhibitors that can lead to resistance. Importantly, we found that ERK inhibitors (which block downstream of MEK inhibitors) could overcome MAPK reactivation and produced enhanced efficacy. Our efforts also identified multiple members of a metabolic and autophagy-regulating pathway, suggesting that autophagy inhibitors (currently in clinical trials for pancreatic cancer) in combination with MAPK inhibitors may be a promising approach. We expect these data to drive new clinical trials for pancreatic cancer patients.