About this Webinar:
Pancreatic ductal adenocarcinoma (PDAC) has one of the lowest survival rates in the Western World. These high levels of mortality are mainly attributed to late diagnosis and limited treatments. Indeed, current therapeutic options still rely on old cytotoxic drugs such as Gemcitabine either alone or in combination with Nab-Paclitaxel. This situation is paradoxical considering the significant progress made during the last two decades in our understanding of PDAC biology, mainly thanks to the development of genetically engineered mouse models that faithfully reproduce the natural history of the human disease. More than 90% of all PDACs are initiated by KRAS mutations follow by inactivation of well-characterized tumor suppressors such as P53, P16/P19 or Smad4. KRAS oncogenes were first identified in human patients in 1982. For over three decades KRAS proteins were thought to be undruggable, until 2013 when Shokat and coworkers identified a small groove in the KRASG12C oncoprotein. That allowed them to insert a small chemotype that when covalently bound to the Cys residue of KRASG12C isoforms, induced regression of lung tumors harboring this mutation.
Based on these pioneering studies, the FDA approved in 2021 the first KRAS inhibitor, Sotorasib, for pretreated KRASG12C positive lung tumor patients. These results led to a frenetic race to develop new KRAS inhibitors either selective against other isoforms such as KRASG12D, as well panKRAS and panRAS inhibitors of wider spectrum. Unfortunately, KRAS inhibitors, so far, have provided somewhat disappointing results primarily due to rapid onset of tumor resistance. In lung tumor patients overall survival is similar to that achieved with classical chemotherapy regiments. In pancreatic cancer, the overall survival of treated patients is just a few months. Hence, the future of KRAS inhibitors will require the development of combination therapies not only to increase their anti-tumor effects but to avoid tumor resistance.
Within these lines, we reasoned that instead of targeting KRAS itself, it might be more efficacious to target its signaling pathways at independent nodes. Subsequent studies with genetically engineered mouse tumors revealed a therapeutic strategy that combined inhibition of three independent signaling nodes involved in downstream (RAF1), upstream (EGFR) and orthogonal (STAT3) KRAS pathways. Genetic elimination of these independent nodes in orthotopic mouse tumor models resulted in their complete and durable regression, leading to tumor-free mice for at least one year. Importantly, this triple targeting strategy did not induce significant toxicities. We are currently trying to validate the efficacy of this therapeutic strategy using pharmacological approaches along with a RAF1 shRNA due to the lack of suitable RAF1 inhibitors. These results may open the door to the development of novel efficacious therapies for PDAC patients.
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