Abstract IA04: Targeting K-Ras signaling in lung and pancreatic adenocarcinomas

Abstract

Abstract K-Ras oncogenes have been implicated in about one fifth of all human cancers including those with the worse prognosis including non-small cell lung carcinoma (NSCLC) and pancreatic ductal adenocarcinoma (PDAC). We have used genetic engineering strategies to develop genetically modified mouse (GEM) models that closely recapitulate the natural history of these human neoplasias. We have used these strains to validate targets of potential therapeutic value with the ultimate goal to translate these findings to the clinic. Briefly, we have crossed these GEM strains with mice that carried conditional knock out mutations in loci encoding potential therapeutic targets. These targets were ablated by genetic means (using inducible recombinases) either at the time of tumor initiation or, whenever possible, once the tumor has been generated. Then, we follow the fate of the tumor in the absence of the target that we wish to validate. This genetic-based strategy has significant advantages over classical pharmacological studies since it does not rely on the quality of the drug/inhibitor. For instance, the observed effects are always mechanism-based and not off-target effects. Moreover, if the target is eliminated systemically, our studies offer relevant information regarding potential toxic effects that may occur when the target would be pharmacologically inhibited in normal tissues. More recently, we are replacing the conditional knock strains by conditional knocked in mice so we will expressing kinase dead isoforms in tumor tissue instead of eliminating the target. We hope that this experimental approach will mimic more accurately those pharmacological responses that will be observed in the clinic. Using these experimental approaches, we have validated each of the K-Ras downstream kinases including those of the Raf/Mek/Erk pathway as well as the cell cycle Cdks. Our results have revealed some unexpected results which may have important implications for the development of future targeted therapies. For instance. whereas c-Raf is essential for the development of lung adenocarcinomas and pancreatic ductal adenocarcinomas, the closely related B-Raf and A-Raf kinases are completely dispensable. Thus demonstrating that K-Ras signaling does not proceed equally through the Raf kinases as previously thought. Likewise, lung adenocarciomas do not progress in the absence of Cdk4. However, ablation of the highly related cell cycle kinases Cdk2 and Cdk6 have no significant effect on tumor development. These observations underscore the need to carry out target validation studies using mouse models of cancer in order to design selective therapies that will have a greater chance of success in the clinic. Finally, we have also validated some upstream signaling effectors, mainly the EGFR for which there are already selective inhibitors in the clinic. Unexpectedly, whereas the EGFR has no therapeutic value in K-Ras driven lung adenocarcinomas as well intestinal tumors (as previously observed in the clinic), it is essential for the initiation of pancreatic tumors. These findings indicate that K-Ras oncogenic signaling may proceed through different effector pathways in a tissue specific manner, a finding that should also help to design more selective therapies. Citation Format: Mariano Barbacid. Targeting K-Ras signaling in lung and pancreatic adenocarcinomas. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr IA04. doi: 10.1158/1557-3125.RASONC14-IA04