Pascal Burri, Assistant Physician for Visceral and Transplant Surgery at University Hospital Zurich, shared a post on LinkedIn:
“Why this PNAS study (Dec 2025) on KRAS-mutant PDAC is more than “strong preclinical data”.
In pancreatic ductal adenocarcinoma, three assumptions have been considered almost unbreakable:
1. KRAS inhibition inevitably leads to rapid resistance.
2. Complete tumor regression is rare, even in preclinical models.
3. Durable control over months is virtually never observed.
This study challenges all three at once.
In orthotopic PDAC models and patient-derived xenografts, a rationally designed combination therapy induced complete tumor regression, with no recurrence and no detectable resistance for more than 200 days. In PDAC biology, this is highly unusual.
The key insight is not therapeutic intensity, but systems-level targeting. KRAS signaling is inhibited while the known adaptive escape routes (EGFR feedback and STAT3-mediated plasticity) are simultaneously blocked. The very mechanisms that typically drive resistance are removed upfront.
Why this matters: PDAC is the stress test of oncology – stroma-rich, highly adaptive, and profoundly therapy-resistant. An approach that does not merely slow growth but eliminates viable escape pathways represents a conceptual shift.
Preclinical is not clinical
But these data provide a biologically coherent rationale for why KRAS-based combination strategies might achieve durable responses in humans – something monotherapies have consistently failed to deliver.
The next step is obvious: carefully designed early-phase clinical trials.
Not driven by optimism, but by biology.
Congratulations to the authors – an impressive and biologically convincing study.”
A targeted combination therapy achieves effective pancreatic cancer regression and prevents tumor resistance
Title: A targeted combination therapy achieves effective pancreatic cancer regression and prevents tumor resistance
Authors: Vasiliki Liaki, Sara Barrambana, Myrto Kostopoulou, Carmen G. Lechuga, Elena Zamorano-Dominguez, Domingo Acosta, Lucia Morales-Cacho, Ruth Álvarez, Pian Sun, Blanca Rosas-Perez, Rebeca Barrero, Silvia Jiménez-Parrado, Alejandra López-García, Marta San Roman, Juan Carlos López-Gil, Matthias Drosten, Bruno Sainz Jr., Monica Musteanu, Eduardo Caleiras, Nelson Dusetti, Valeria Poli, Francisco Sánchez-Bueno, Carmen Guerra, Mariano Barbacid
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