A targeted combination therapy achieves effective pancreatic cancer regression and prevents tumor resistance
Menée à l'aide de modèles murins et de xénogreffes d'adénocarcinomes canalaires du pancréas, cette étude met en évidence l'intérêt d'un traitement combinant trois inhibiteurs sélectifs de KRAS (daraxonrasib, afatinib et SD36) pour induire la régression de la tumeur et prévenir la résistance thérapeutique des cellules cancéreuses
The development of RAS inhibitors represents a major advance in the treatment of KRAS-driven pancreatic ductal adenocarcinoma (PDAC). RAS(ON) inhibitors such as daraxonrasib (RMC-6236) have led to significant improvements in survival compared to historical data. Unfortunately, the rapid onset of tumor resistance has thwarted their therapeutic benefit. This study describes a triple combination therapy made of daraxonrasib along with afatinib, an irreversible EGFR/HER2 kinase inhibitor and SD36, a selective STAT3 PROTAC that induces the robust regression of experimental PDACs and avoids the onset of tumor resistance. This triple combination is well tolerated in mice. Taken together, these studies open the road to design novel combination therapies that may improve the survival of PDAC patients. Pancreatic ductal adenocarcinoma (PDAC) has one of the lowest cancer survival rates. Recent studies using RAS inhibitors have opened the door to more efficacious therapies, although their beneficial effect is still limited mainly due to the rapid appearance of tumor resistance. 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 regression of orthotopic PDACs induced by KRAS/TP53 mutations. Likewise, a combination of selective inhibitors of KRAS (RMC-6236/daraxonrasib), EGFR family (afatinib), and STAT3 (SD36) induced the complete regression of orthotopic PDAC tumors with no evidence of tumor resistance for over 200 d posttreatment. 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. Of importance, this combination therapy was well tolerated. In sum, these results should guide the development of new clinical trials that may benefit PDAC patients.
Proceedings of the National Academy of Sciences , résumé, 2025