Abstract 4774: Inhibition of pancreatic acinar ductal metaplasia by novel YAP/TAZ inhibitor, CV-4-26

Abstract Current challenges for pancreatic ductal adenocarcinoma (PDAC) treatment include overcoming the disease’s fibrous tumor microenvironment with limited cytotoxicity- in which tissue stiffening is believed to occur even pre-disease onset. Acinar to ductal metaplasia (ADM), the transdifferentiation of acinar cells into duct-like cells, is a predisposing event to PDAC development that is also linked to Hippo signaling, a major pathway involved in fibrosis and inflammation. Hippo activation is initiated by the yes-associated protein (YAP) in conjunction with the PDAZ binding motif (TAZ) and TEA domain (TEAD) transcription factor. Thus, the synthesis of the novel covalent TEAD autopalmitoylation inhibitor, CV-4-26, presented an opportunity to therapeutically target ADM. CV-4-26 binds to the TEAD lipid binding pocket, which, in turns, hinders TEAD palmitoylation, thereby leading to the inhibition of the Hippo pathway. Utilizing our 3D organoid p48Cre/+LSL-KRASG12D/+ (KC) mouse model, we demonstrated pronounced phenotypic and molecular inhibition of ADM by CV-4-26, resulting in a conserved acinar phenotype, as well as downregulation of downstream markers of the YAP/TAZ complex. The compound did not reverse ADM to the acinar state once ducts were visibly formed. Yet, CV-4-26 demonstrated a lack of cytotoxicity (up to 25 µM) as determined by Calcein AM staining. Biomechanical measurements of extracellular matrix stiffness acquired through calculations of fluorescent nanoparticle displacement further displayed decreased moduli as a response to inhibition treatment. Moreover, a 56-fold downregulation of collagen (COL1A1, COL1A2) mRNA, markers for PDAC development, was observed. However, less reduction in the collagens and extracellular matrix stiffness was observed in the ADM reversal treatments, corroborating our morphology and gene expression results. Our data suggest that combining CV-4-26 by ADM inhibition with standard of care therapies for PDAC may enhance the penetration of small molecules through the tumor’s extracellular matrix. Citation Format: Corey M. Perkins, Chen Zhou, Martha Campbell-Thompson, Yating Mao, Kalina R. Atanasova, Jinmai Jiang, Ranjala Ratnayake, Hendrik Luesch, Jamel Ali, Chenglong Li, Thomas D. Schmittgen. Inhibition of pancreatic acinar ductal metaplasia by novel YAP/TAZ inhibitor, CV-4-26 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4774.