Abstract A086: FAK inhibition improves CD40 agonist immunotherapy response and reduces MAPK signaling in pancreatic ductal adenocarcinoma

Abstract Immunotherapy efficacy is limited in pancreatic ductal adenocarcinoma (PDA), due in part to the development of resistance mechanisms. Thus, additional agents are required for overcoming resistance and achieving durable therapeutic benefit. Anti-CD40 agonist immunotherapy (CD40) has shown limited antitumor activity in patients with cancer indicating the need to identify strategies to overcome resistance. Here, we investigated how inhibition of focal adhesion kinase (FAKi) enhances the response to CD40 agonist immunotherapy. Subcutaneous PDA mouse models were used to study treatment efficacy. Gene expression analysis was performed on tumors using bulk RNA-sequencing and pathway enrichment analysis via Gene Ontology: Biological Process. Mice were dosed with CD40 once via intraperitoneal injection and with FAKi twice-daily via oral gavage. While CD40 prolonged survival compared to vehicle controls (median survival 43 vs 32 days, P<0.0001), treatment did not achieve complete regression. However, CD40 induced transient tumor control before outgrowth (tumor weight 0.247 g vs 0.03 g, P=0.02), indicating the development of resistance. To investigate mechanisms of resistance, we assessed transcriptional data and observed increased RAS/MAPK signaling in CD40 treated tumors compared to controls (RAS protein signal transduction, NES 2.81; Regulation of ERK1 and ERK2 cascade, NES 2.67; Regulation of MAPK cascade, NES 2.3). These data suggest that RAS/MAPK signaling plays a role in resistance to CD40 agonist therapy and that targeting this pathway can improve CD40 response. FAK activation drives MAPK signaling and is frequently hyperactivated in PDA, supporting the use of FAK inhibition to modulate MAPK pathway activity. In contrast to CD40 alone, CD40 with FAKi reduced MAPK pathway activity (Regulation of ERK1 and ERK2 cascade, NES -1.58; Regulation of MAPK cascade, NES -1.58 compared to control). Treatment with FAKi and CD40 prolonged survival compared to CD40 alone (median survival 75 vs 43 days, P<0.0001). Notably, 20% of mice treated with FAKi and CD40 maintained complete regression at study endpoint (122 days), while no survivors were present at study end when treated with CD40 or FAKi individually. CD40 with FAKi increased tumor necrosis compared to control (18.52 vs 4.41% of tumor area, p=0.02), while CD40 or FAKi individually only modestly induced tumor necrosis (6.60 and 7.44% of tumor area). FAKi with CD40 also reduced the proportion of tumor cells within the tumor compared to CD40 alone (10.14 vs 35.60 CK19+ % of tumor ROI area, P<0.001). Additionally, combining FAKi with CD40 produced anti-tumor activity as seen by reduction in tumor weights in tumors previously identified as high MAPK signaling and non-responsive to CD40 (0.849 g vs 0.124 g for control and CD40 + FAKi, respectively, P = 0.008). These data indicate that FAKi sensitizes non-responsive tumors to immunotherapy. These studies demonstrate the therapeutic benefit of combining CD40 agonist immunotherapy with FAKi. Citation Format: Anna S. Thickens, Meredith L. Stone, Yan Li, Heather Coho, John C. McVey, Kelly Markowitz, Andrew Schmidt, Kathleen Graham, Silvia Coma, Devora Delman, Jonathan Pachter, Gregory Beatty. FAK inhibition improves CD40 agonist immunotherapy response and reduces MAPK signaling in pancreatic ductal adenocarcinoma [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 A086.