Abstract Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive cancer with a five-year survival rate of 13. 3%, and existing standard-of-care therapies provide only limited benefit. Recent advances in RAS-targeted therapies offer promising prospects for more effective treatment options in this KRAS-driven malignancy. Previously we have shown that therapeutic induction of cellular senescence as a consequence of RAS pathway targeting therapies can activate cytokine production and enhance antigen presentation through the senescence-associated secretory phenotype (SASP) to facilitate innate and adaptive immunity against KRAS mutant cancers. Intriguingly, whereas treatment with a combination of MEK and CDK4/6 inhibitors could induce NK cell-mediated tumor regressions and long-term survival responses in genetically engineered mouse models (GEMMs) of KRAS mutant lung cancer, these therapies were not sufficient to achieve anti-tumor immune responses in PDAC. We found that alphaSMA+ myofibroblasts that contribute to the predominant desmoplastic response and chemoresistance in PDAC also inhibit the SASP production from tumor cells following therapy-induced senescence, and that their genetic removal could enhance pro-inflammatory SASP cytokine levels and NK and CD8+ T cell immunity in PDAC. Indeed, conditioned media from CAFs could inhibit senescence and SASP induction in KPC murine tumor cells in vitro. Mechanistically, fractionation and recombinant protein experiments revealed that a number of growth factors highly expressed by CAFs contributed to senescence bypass, and that small molecules inhibiting their downstream signaling could restore senescence-mediated growth arrest. Our results show that CAFs can contribute to RAS pathway inhibitor resistance by dampening senescence and subsequent SASP responses that drive anti-tumor immunity, and that targeting CAF-tumor cell crosstalk could lead to effective combination therapies to enhance RAS inhibitor outcomes. Citation Format: Boyang Ma, Marcus Ruscetti. Cancer-associated fibroblast (CAF) crosstalk with tumor cells bypasses cellular senescence and dampens responses to RAS pathway targeted therapy in PDAC abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85 (18Suppl₃): Abstract nr A077.
Ma et al. (2025) studied this question.