Abstract A058: The Influence of WDR-62 in c-Jun-N-terminal Kinase on the Spatiotemporal Regulation of JNK Activation in Pancreatic Ductal Adenocarcinoma

c-Jun N-terminal kinase activation plays a significant role in dictating cell fate outcome. In response to cellular stress inducers, hydrogen peroxide. Biochemically, the p38 and JNK-MAPK can activate the SAPK (stress-activated protein kinase) pathways. This same stress granule can also reduce the SAPK apoptotic response. Where the RACK-1 (Receptor for C kinase-I) functions as a binding agent to initiate the stress granule signaling pathway. In normal human microenvironments, JNK isoforms have been found responsible for showcasing tumor suppressive characteristics. Similarly, the JNK and Harvey Rat Sarcoma Virus can also initiate genetic screenings in mice with the KRASG-12D allele and Pdx1-Cre transgene. Normally, PDAC is an aggressive malignancy with a survival rate of only 13%. The inactivation of the drug, multi-drug resistance, cell death inhibition (apoptosis suppression), altering in the drug metabolism, epigenetic changes, and changes in the drug targets can lead to the development of high resistance against oxaliplatin. This aggressive form of malignancy mostly results in missense mutation, especially at the thermodynamically active sequences of the Kirsten Rat Sarcoma Virus such as G12D, G12V, and Q61H. However, our primary focus is G12D. The oxaliplatin-led chemoresistance in both cell-autonomous and non-autonomous secretions of the 15dPGJ2 prostaglandin has been proposed to facilitate the development of the PDAC. Similar to JNK, the WD Repeat Domain 62 (WDR-62) may also lead to the development of pancreatic ductal adenocarcinoma (PDAC). WDR-62 functions as a novel JNK (c-Jun N-terminal kinase) binding protein, has only been expressed in heat-sensitive circumstances, and is a part of the mitogen-activated protein kinase pathway (MAPK). WDR-62 is a 175 kDa-long protein that binds to the JNK and alters the MAPK signaling cascade. As a novel scaffold protein, WDR-62 can bind with other scaffolds such as JIP-1, JIP-2, and JIP-3 to control the overexpression of stress granules in PDAC. The WDR-62 inhibits the AP-1 transcription through the recruitment of the JNK to a non-nuclear compartment. Moreover, JNK and WDR-62 can regulate the dynamic interplay between the stress granules, thereby mediating the mRNA-generated stresses. In general, the stress granules and 15d-PGJ2 prostaglandin have been suggested to regulate the regional and time-specific JNK activations. WDR-62 leads to phosphorylation, activating the classical, non-classical, and overexpression of the stress granules and the expression of TIA (tumor-induced angiogenesis) and TTP (thrombotic thrombocytopenic purpura). We hypothesize the knockdown of the WDR-62 can lead to the suppression of theOxaliplatin-resistant WDR62 gene-initiated DNA repairing system and the regulation of the normal cell signaling process of the MAPK, cell proliferation, apoptosis, and mRNA homeostasis in PDAC. However, in our studies we have found the less limited role of the WDR-62 in the development of PDAC, and the expression of the spatiotemporal regulation of the JNK is only active till 8.5 hours. Citation Format: SDANISH KADIR, Partha R. Laskar. The Influence of WDR-62 in c-Jun-N-terminal Kinase on the Spatiotemporal Regulation of JNK Activation 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): nr A058.