Abstract B101: TNFR-MK2 Signaling Drives Autophagy and Resistance to KRAS/MAPK Inhibition in Pancreatic Cancer

Abstract The upregulation of inflammatory signaling is a hallmark of pancreatic ductal adenocarcinoma (PDAC) and plays a central role in promoting resistance to targeted therapies. In this study, we demonstrate that inhibition of the mitogen-activated protein kinase (MAPK) pathway or mutant KRAS in PDAC cells induces tumor necrosis factor-α (TNFα) secretion, which in turn activates autocrine TNF receptor (TNFR) signaling. Silencing TNFR significantly reduces the pro-apoptotic effects of MEK or ERK inhibitors, indicating that TNFR signaling is essential for the cytotoxic activity of MAPK-targeted therapies.We identify MAPKAPK2 (MK2) as a critical downstream effector of TNFR signaling that supports PDAC cell survival following MAPK inhibition. MK2 exerts its function, in part, through phosphorylation of heat shock protein 27 (Hsp27), a stress response protein involved in cytoprotection. Transcriptomic analysis revealed that MK2 inhibition leads to a broad downregulation of inflammatory gene programs and simultaneously suppresses autophagy—a known mechanism of resistance to KRAS and MAPK inhibitors.Mechanistically, we show that TNFR signaling activates the unfolded protein response (UPR), a cellular stress pathway necessary for autophagy induction. Moreover, MK2 directly phosphorylates several key autophagy regulators, including Beclin1, AMPKα, and ULK1, further establishing its role as a central mediator of protective autophagy in PDAC. These findings reveal a novel TNFR-MK2–UPR–autophagy axis that facilitates tumor cell survival under therapeutic pressure.Therapeutically, combining the MK2 inhibitor ATI-450 with MEK, ERK, or KRAS inhibitors resulted in more effective tumor suppression in human PDAC xenograft models compared to monotherapy. In an aggressive autochthonous PDAC mouse model, this combination significantly extended overall survival and delayed tumor progression.In conclusion, our findings highlight TNFR-MK2 signaling as a key adaptive pathway that enables PDAC cells to resist MAPK and KRAS-targeted therapies by promoting autophagy. Targeting MK2 in combination with existing inhibitors disrupts this protective mechanism and enhances treatment efficacy. These results provide strong rationale for the clinical evaluation of MK2 inhibitors in combination therapy regimens for PDAC patients. Citation Format: Ofejiro B. Pereye, Iftikhar A. Khawar, Qing Wei, Richard Kurupi, Vikas K. Somani, Ashenafi Bulle, Sapana Bansod, Timothy Hung-Po. Chen, Lin Li, Patrick M. Grierson, Joseph B. Monahan, Paul S. Changelian, Marianna B. Ruzinova, Mallory K. Roach, Kirsten Bryant, Kian-Huat Lim. TNFR-MK2 Signaling Drives Autophagy and Resistance to KRAS/MAPK Inhibition in Pancreatic Cancer [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 B101.