Abstract A077: Cancer-associated fibroblast (CAF) crosstalk with tumor cells bypasses cellular senescence and dampens responses to RAS pathway targeted therapy in PDAC

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(18_Suppl_3):Abstract nr A077.