Pancreatic ductal adenocarcinoma (PDAC) has one of the lowest cancer survival rates. Recent studies using RAS(ON) inhibitors as single agents have opened the door to more efficacious therapies. Here, we demonstrate that genetic ablation of three independent nodes involved in downstream (RAF1), upstream (EGFR) and orthogonal (STAT3) KRAS signaling pathways leads to complete and permanent disappearance of orthotopic PDACs induced by KRAS/TP53 mutations. Likewise, a combination of RAS(ON) (RMC-6236/daraxonrasib), EGFR family (afatinib) and STAT3 (SD36) selective inhibitors/degraders induced the effective regression of these orthotopic tumors with no evidence of tumor resistance for over 200 days post-treatment. This combination therapy also led to significant regression of genetically engineered mouse tumors as well as patient-derived tumor xenografts (PDX) in the absence of tumor relapses. Finally, this combination therapy was well tolerated by the animals. These results should guide the development of clinical trials that could benefit PDAC patients.
Liaki et al. (Mon,) studied this question.