Abstract PL03-01: Targeting K-RAS driven cancer

Abstract

Abstract K-RAS oncogenes have been implicated in about one fifth of all human cancers including lung adenocarcinoma and pancreatic ductal adenocarcinoma, two tumor types with some of the worse prognosis. In order to identify effective therapeutic strategies to treat these tumors, we have developed genetically engineered mouse (GEM) models that closely recapitulate their natural history. We are using these mice to validate targets of potential therapeutic value with the ultimate goal to translate these findings to the clinic. In previous studies, we have crossed these GEM models with mice that carried either germ line or lox-Cre conditional knock out loci encoding each of the downstream kinases of the Raf/Mek/Erk pathway as well as the cell cycle interphase Cdks to interrogate their role in the development of K-Ras driven lung adenocarcinomas. These studies have led us to validate the c-Raf and Cdk4 kinases as essential targets for these tumors (Puyol et al., Cancer Cell 2010; Blasco et al., Cancer Cell 2011). Following a similar strategy, we have demonstrated that the EGF Receptor and c-Raf were also absolutely essential for the development of pancreatic ductal adenocarcinomas (Navas et al., Cancer Cell 2012). Importantly, systemic ablation of either c-Raf or Cdk4 has no significant effect on normal homeostasis. Now, we have decided to interrogate the role of these targets in advanced tumors. To this end, we have generated new GEM models in which expression of the resident K-Ras oncogene, as well as ablation of the p53 tumor suppressor is mediated by the frt-FLp(o) targeting system, a strategy that allows temporal separation of tumor development from target ablation. In addition, we have generated lox-Cre based conditional knock-in strains that upon recombination direct the expression of kinase dead isoforms instead of inducing protein ablation. We feel that these strains should serve as better models to mimic drug intervention in the clinic. Finally, we are now combining ablation (or inactivation) of these targets in order to identify combinations that may eventually eradicate advanced tumors. We hope that these studies will serve to guide the design of future clinical trails to treat patients carrying K-RAS mutant tumors. Citation Format: Mariano Barbacid. Targeting K-RAS driven cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr PL03-01.