Exploring the therapeutic effect of targeting KRAS and STAT3 in pancreatic ductal adenocarcinoma

• Autores: Lucía Morales Cacho
• Directores de la Tesis: Mariano Barbacid Montalbán (dir. tes.), Carmen Guerra González (dir. tes.)
• Lectura: En la Universidad Autónoma de Madrid ( España ) en 2023
• Idioma: inglés
• Número de páginas: 219
• Títulos paralelos:
  • Investigación del efecto de KRAS y STAT3 como dianas terapéuticas contra el adenocarcinoma ductal de páncreas
• Enlaces
  • Tesis en acceso abierto en: Biblos-e Archivo
• Resumen

  • Pancreatic Ductal Adenocarcinoma (PDAC) is one of the cancer types with higher mortality mainly caused by its late diagnosis and the lack of effective treatment. Therefore, there is an urgent need to develop novel and more efficacious strategies against PDAC. In this thesis we have studied the therapeutic effect and derived toxicities of the systemic elimination of two potential therapeutic targets: KRAS and STAT3. After decades of considering KRAS undruggable, specific inhibitors of KRASG12C and KRASG12D have been recently developed. However, not all the patients answer to these inhibitors and for the ones that respond, resistance has arisen in clinical trials. Furthermore, there are no inhibitors to target all the KRAS oncogenic mutations. Pan-KRAS inhibitors are currently under development, but it is necessary to anticipate potential secondary effects of inhibiting total KRAS as well as resistance mechanisms that might arise. In this thesis, we have observed that systemic genetic elimination of KRAS in adulthood results in development of myelomonocytic metaplasia. However, we could conclude that mice seem to be healthy up to 12 months of KRAS elimination, opening the door to the safe use of pan-KRAS inhibitors. In order to identify other mechanisms of resistance to oncogenic KRAS inhibition, we have performed therapeutic studies with a genetically engineered mouse model of PDAC. Genetic ablation of KRASG12V resulted in most of the tumors showing stabilization or regression, followed by tumor relapse caused by the presence of tumor cells that escape the oncogene elimination thanks to the accumulation of several copies of the allele, and of KRAS-independent cells. Additionally, a single KRAS-independent subclone was isolated in vitro. In both cases, these cells bypass KRAS addiction by adopting a more aggressive behavior, that includes changes in morphology and cell adhesion (more mesenchymal-like) and rewiring of proliferative, metabolic and survival pathways. Some proteins involved in these changes could be candidates for combined treatment with KRAS inhibitors. An alternative strategy to directly inhibiting KRAS has been the targeting of different members of the RAS signaling pathways. Previous work has demonstrated that half of the PDACs regress upon elimination of Egfr and Raf1. However, we have observed that this proportion is reduced in bigger tumors, showing that intratumor heterogeneity increases with tumor progression and highlighting the need to identify the mechanism of resistance to the ablation of these two genes. By characterization of molecular signaling, STAT3 was identified as the key mediator of the resistance to the elimination of Egfr and Raf1. Although we have observed that the systemic genetic elimination of STAT3 results in lethality due to the breakdown of the epithelial intestinal barrier, its pharmacological elimination with a PROTAC is not toxic. Therefore, STAT3 inhibition can still be considered as a therapeutic target. Several new engineered Stat3 alleles have been designed as part of this thesis in order to perform genetic in vivo studies without the toxicity derived from the elimination of STAT3. Interestingly, these models showed that overexpression of STAT3 is also toxic due to systemic inflammation, so the levels of STAT3 must be carefully controlled in order to maintain the homeostasis