Exploring novel therapeutic strategies against Kras-driven advanced pancreatic adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by complex mutational landscape and heterogeneous oncogenic signaling. Therefore, concurrent inhibition of different pathways remains a significant challenge. Most of the therapeutic studies with genetically engineered mouse models (GEMMs), only reveal the preventive role of genes, as their deletion is performed at the stages of PDAC initiation. However, a recently developed PDAC therapeutic mouse model enables the study of the curative function of genes, as it allows genetic deletion of the targets in fully developed tumors. Not long ago, it was demonstrated that genetic ablation of Egfr and Raf1, two critical mediators of the KRAS signaling pathway, results in complete regression of a significant fraction of Kras/Trp53 driven tumors of small sizes. Importantly, this regression was achieved with very low toxicity. Yet, tumors of bigger sizes remained refractory to this combined deletion. In this thesis we have studied the mechanism that drives resistance in tumors that do not respond to the elimination of Egfr and Raf1. We have performed OMIC studies (RNAseq and phospho-proteomics) to compare in vitro tumors that respond differently to this combined elimination, Responder (R) and Non responder (NR) cells. Based on their transcription pattern, we have established a molecular signature to identify Responder and Non responder tumors. We have characterized the different molecular signaling of these two groups of tumor cells and more importantly, we have identified X as the key mediator of the resistant mechanism. Indeed, combined in vivo and in vitro elimination of Egfr, Raf1 and X leads to complete regression of tumors induced by Kras/Trp53 mutations. Therefore, we have developed a promising therapeutic strategy for NR PDACs based on the simultaneous inhibition of three targets (Egfr, Raf1 and X). We also identified a mechanism of resistance to this therapeutic strategy for a specific group of tumors. Concretely, PDACs that exhibit loss of the Kras wild type allele as well as high amplification of the mutant allele are not affected by the combined elimination of Egfr, Raf1 and X. Interestingly, these tumoral cell populations have increased metastatic potential and unique transcriptional profile. Thus, further studies will reveal the mechanism of metastasis and will indicate potential hits to target this aggressive tumoral population. Overall, in this thesis we describe and provide evidence of a novel therapeutic strategy based on the combined targeting of EGFR, RAF1 and X. Additionally, we suggest that allelic imbalances of wild type and mutant KRAS need to be taken into consideration for the design of future therapeutic strategies against pancreatic cancer