TARGETING KRAS SIGNALING AT THREE INDEPENDENT NODES LEADS TO COMPLETE AND DURABLE PANCREATIC CANCER REGRESSION [RNA-seq]
Pancreatic ductal adenocarcinoma (PDAC) has one of the lowest cancer survival rates. Although KRAS oncogenes are responsible for the initiation of most PDACs, thus far KRAS inhibitors have not changed their clinical outcome. Here, we describe a therapeutic strategy that combines inhibition of three independent signaling nodes involved in downstream (RAF1), upstream (EGFR) and orthogonal (STAT3) KRAS signaling pathways. Genetic elimination and/or pharmacological inhibition/degradation of these independent nodes in orthotopic mouse tumor models results in their complete and durable regression.  The efficacy of this therapeutic strategy has also been validated in several patient-derived organoid (PDO) and xenograft (PDX) PDAC tumor models using a combination of a Pan-ERBB inhibitor (Afatinib), a selective STAT3 PROTAC (SD36) and a RAF1 shRNA. Importantly, this triple strategy did not induce significant toxicities. These results open the door to the development of novel targeted therapies for PDAC patients. Overall design: We explanted mouse Pancreatic Ductal Adenocarcinomas (PDACs) in culture from 27 different tumors. All 27 cultures were infected with Adeno-GFP viral particles.  We then performed gene expression profiling of the 27 PDAC cultures infected with Adeno-GFP viral particles. 14 of those tumors were also infected with Adeno-CRE viral particles, for the genetic elimination of the floxed alleles Egfr and Raf1. We also performed differential expression analysis of the 14 PDAC cultures treated with Adeno-GFP vs Adeno-CRE viral particles, to detect differences before and after elimination of Egfr and Raf1.