by Kaykobad Hossain
This week’s journal club focuses on a study from PNAS (2025) proposing that coordinated multi-node inhibition can achieve deep and durable pancreatic tumor regression.
Pancreatic ductal adenocarcinoma (PDAC) has one of the highest mortality rates among all the cancer types. Current studies using RAS inhibitors have resulted in more efficacious therapy, however, rapid emergence of tumor resistance is still a vital limitation to this therapy. In this study, the researchers propose that long-lasting tumor control requires simultaneous inhibition of multiple critical signaling nodes within the KRAS network rather than targeting KRAS alone.
To prevent resistance, this study identifies three key pathways that must be blocked: direct KRAS signaling, upstream receptor tyrosine kinases (EGFR), and STAT3-mediated survival signaling. These interconnected pathways allow tumor cells to bypass single-agent therapies. To test their hypothesis, the researchers used a triple combination consisting of daraxonrasib (RMC-6236), a KRAS(ON) inhibitor; afatinib, an EGFR/HER2 inhibitor; and SD36, a STAT3-targeting PROTAC degrader. The regimen was evaluated in multiple preclinical models, including genetically engineered mice and patient-derived xenografts.
The researchers have discovered that while mono and double combination therapies produced only partial and transient tumor shrinkage, the triple combination induced complete regression of established tumors in several models. Importantly, tumors did not recur for more than 200 days after treatment cessation, suggesting consistent disease control rather than temporary suppression. The therapy was also reported to be well tolerated in animal models.
Mechanistic analyses showed that inhibiting a single pathway triggers compensatory feedback loops, enabling tumor survival. By simultaneously blocking KRAS, EGFR, and STAT3, the combination therapy effectively eliminated the main escape routes available to cancer cells and thus prevents resistance from emerging. Genetic experiments confirmed that only concurrent disruption of these interconnected pathways resulted in sustained tumor eradication.
Overall, the study provides strong preclinical evidence that coordinated multi-node inhibition can achieve deep and durable pancreatic tumor regression while preventing adaptive resistance, offering a promising framework for future clinical strategies.
Continue your reading here:
A targeted combination therapy achieves effective pancreatic cancer regression and prevents tumor resistance
Liaki V, Barrambana S, Kostopoulou M, Lechuga CG, Zamorano-Dominguez E, Acosta D, Morales-Cacho L, Álvarez R, Sun P, Rosas-Perez B, Barrero R, Jiménez-Parrado S, López-García A, San Roman M, López-Gil JC, Drosten M, Sainz B Jr, Musteanu M, Caleiras E, Dusetti N, Poli V, Sánchez-Bueno F, Guerra C, Barbacid M.
Proc Natl Acad Sci U S A 2025 Dec 9;122(49):e2523039122. doi: 10.1073/pnas.2523039122. Epub 2025 Dec 2