Abstract 2709: Disrupting cancer fitness and pro-tumorigenic fibroblast functions with a first-in-class Pin1 degrader

Abstract Background: Pin1 plays a pivotal role in regulating cellular processes including growth and differentiation by catalyzing the cis-trans isomerization of peptidyl-prolyl bonds in phosphorylated proteins. As a key gene involved in cancer cell fitness, Pin1 promotes tumor progression and maintains the immunosuppressive tumor niche. Research has extensively documented how Pin1 acts as a catalyst in both the initiation and progression of malignancies by modulating the stability and activity of oncogenes and tumor suppressors such as p53, c-Myc and NF-κB. These interactions underline Pin1's significant role in the intrinsic biology of cancer, influencing cell cycle progression, apoptosis, and cellular senescence. Beyond its direct effects on cancer cell intrinsic pathways, Pin1's influence extends to the tumor microenvironment, the supportive niche a tumor creates to support growth and metastasis. Recent studies have identified Pin1 as a driver of cancer-associated fibroblast (CAF)-mediated suppression, particularly in colorectal cancer, breast cancer and pancreatic cancer. In this study, we present the discovery of a reversible, first-in-class Pin1 degrader. Our findings reveal how Pin1 degradation not only disrupts cancer cell fitness but also reprograms fibroblast phenotypes. Methods: Our research employed a set of in vitro experiments with Pin1-targeting strategies applied to various colorectal cancer and fibroblast cell lines. The impact on the cancer fitness and fibroblast phenotypes was assessed through a detailed cell phenotype and protein analysis using a combination of imaging analysis, ELISA, and Western Blot techniques. Results: We demonstrate that targeting Pin1 significantly reprogrammed fibroblast phenotypes, steering them away from a pro-tumorigenic state. We disclose a first-in-class selective Pin1 degrader which phenocopies knockout effects on CAF and cancer cell interactions. We further show that Pin1 degradation or KO has a profound impact on multiple drivers of tumor fitness and fibroblast-mediated suppression. Notably, Pin1 degradation disrupts cancer cell communication with their surrounding microenvironment, leading to reduced tumor growth and decreased survival. Conclusions: These findings highlight Pin1's pivotal role in driving critical cellular and molecular mechanisms in cancer. Our study demonstrates the potential of a bifunctional Pin1 degrader to selectively and efficiently target Pin1 in both CAFs and cancer cells, altering CAF phenotypes and disrupting mechanisms essential for cancer cell fitness and viability. Citation Format: Melvyn Chow, Morgan O'Shea, Lilly Ein, Julie Arnold, Sydney Alnemy, Erica Dube, Pradeep Kota, Guosen Ye, Ronan Hanley, Andrew Good, Kristin Brown, Catherine Sabatos-Peyton, Emily Corse, Sebastian Hayes, Krista Goodman. Disrupting cancer fitness and pro-tumorigenic fibroblast functions with a first-in-class Pin1 degrader [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2709.