Thirty-seven years after the identification of the KRAS oncogene in a significant fraction of human tumors (mainly pancreas, colorectal and lung carcinomas), and no selective inhibitors have been approved by the FDA, a problem that represents a major health issue. Recently, the identification of selective inhibitors against the KRASG12C isoform has generated great excitement and at least two compounds are already in phase I/II clinical trials. Yet, this mutation only represents a small fraction of all KRAS mutant tumors, mainly in lung adenocarcinomas.
Our laboratory is interested in identifying viable therapeutic strategies against KRAS mutant pancreatic and lung adenocarcinomas, two tumor types in which there is overwhelming evidence that KRAS mutations represent the initiating cancer-triggering event. To this end, we have embarked in a long-term project to validate the therapeutic potential of each member of the MAPK and PI3K pathways, the main signaling pathways responsible for transmitting KRAS oncogenic signaling, using genetically engineered mouse models that faithfully reproduce the natural history of the corresponding human tumors.
This work has led to the demonstration that tampering with these signaling pathways is unacceptably toxic for mice, a result that may explain the failure of panRAF, panMEK, and panERK inhibitors in a battery of clinical trials. Similar results have been obtained upon genetic inactivation of PIK3CA and mTOR kinase activity. In contrast, we have identified RAF1 as an essential signaling element for KRAS/TP53 driven lung and pancreatic tumors. Ablation of RAF1 alone results in regression of 2/3 of advanced Kras/Trp53-driven lung adenocarcinomas (Sanclemente et al., Cancer Cell 2018). Moreover, combined ablation of RAF1 and EGF Receptors resulted in the complete regression of a significant percentage of Kras/Trp53 mutant pancreatic ductal adenocarcinomas, the first time that this is observed even in experimental tumor models (Blasco et al., Cancer Cell, 2019). Equally important, although RAF1 expression is essential for embryonic development, its systemic ablation in adult mice does not result in significant toxic consequences.
We are currently engaged in two main lines of research. To identify additional non-toxic targets to increase the percentage of tumor regressions in both lung and pancreatic tumors and to generate suitable RAF1 inhibitors capable of reproducing pharmacologically those therapeutic effects observed upon its genetic ablation. To this end, our group has succeeded in expressing RAF1 in a soluble form. This result will allow us to identify small molecules that can bind to RAF1 in order to ultimately, generate PROTACs to degrade RAF1 in human tumors. The Barbacid laboratory is fully committed to translate the basic findings obtained with genetically engineered mouse tumor models to a clinical scenario that eventually will help patients suffering from KRAS mutant cancers.