1. Targeting Pin1 renders pancreatic cancer eradicable by synergizing with immunochemotherapy.
- Author
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Koikawa K, Kibe S, Suizu F, Sekino N, Kim N, Manz TD, Pinch BJ, Akshinthala D, Verma A, Gaglia G, Nezu Y, Ke S, Qiu C, Ohuchida K, Oda Y, Lee TH, Wegiel B, Clohessy JG, London N, Santagata S, Wulf GM, Hidalgo M, Muthuswamy SK, Nakamura M, Gray NS, Zhou XZ, and Lu KP
- Subjects
- Adaptor Proteins, Signal Transducing chemistry, Adaptor Proteins, Signal Transducing metabolism, Adenocarcinoma drug therapy, Adenocarcinoma immunology, Adenocarcinoma pathology, Allografts immunology, Amino Acid Motifs, Animals, Apoptosis drug effects, B7-H1 Antigen metabolism, Cancer-Associated Fibroblasts metabolism, Cancer-Associated Fibroblasts pathology, Carcinoma, Pancreatic Ductal drug therapy, Carcinoma, Pancreatic Ductal immunology, Carcinoma, Pancreatic Ductal pathology, Cell Line, Tumor, Cell Membrane drug effects, Cell Membrane metabolism, Deoxycytidine analogs & derivatives, Deoxycytidine pharmacology, Deoxycytidine therapeutic use, Drug Synergism, Endocytosis drug effects, Equilibrative Nucleoside Transporter 1 metabolism, Humans, Immunosuppression Therapy, Lysosomes drug effects, Lysosomes metabolism, Mice, Microfilament Proteins chemistry, Microfilament Proteins metabolism, Oncogenes, Organoids drug effects, Organoids pathology, Signal Transduction drug effects, Survival Analysis, Tumor Microenvironment drug effects, Xenograft Model Antitumor Assays, Gemcitabine, Immunotherapy, Molecular Targeted Therapy, NIMA-Interacting Peptidylprolyl Isomerase metabolism, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms immunology
- Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by notorious resistance to current therapies attributed to inherent tumor heterogeneity and highly desmoplastic and immunosuppressive tumor microenvironment (TME). Unique proline isomerase Pin1 regulates multiple cancer pathways, but its role in the TME and cancer immunotherapy is unknown. Here, we find that Pin1 is overexpressed both in cancer cells and cancer-associated fibroblasts (CAFs) and correlates with poor survival in PDAC patients. Targeting Pin1 using clinically available drugs induces complete elimination or sustained remissions of aggressive PDAC by synergizing with anti-PD-1 and gemcitabine in diverse model systems. Mechanistically, Pin1 drives the desmoplastic and immunosuppressive TME by acting on CAFs and induces lysosomal degradation of the PD-1 ligand PD-L1 and the gemcitabine transporter ENT1 in cancer cells, besides activating multiple cancer pathways. Thus, Pin1 inhibition simultaneously blocks multiple cancer pathways, disrupts the desmoplastic and immunosuppressive TME, and upregulates PD-L1 and ENT1, rendering PDAC eradicable by immunochemotherapy., Competing Interests: Declaration of interests K.K., G.M.W., T.D.M., B.J.P., N.L., N.S.G., X.Z.Z., and/or K.P.L. are inventors of a number of issued patents and/or pending patent applications on Pin1, Pin1 biomarkers, Pin1 inhibitors, and Pin1 inhibitor combination to treat human diseases; X.Z.Z. and K.P.L. are inventors of cis P-tau antibody technology, which was licensed by BIDMC to the startup Pinteon Therapeutics. X.Z.Z. and K.P.L. are the scientific founders and former scientific advisors of and own equity in Pinteon. Their interests were reviewed and are managed by BIDMC in accordance with its conflict of interest policy. G.M.W. reports research funding from Glaxo Smith Kline (institutional funding). N.S.G. is a founder, science advisory board member (SAB), and equity holder in Gatekeeper, Syros, C4, Allorion, Jengu, Inception, B2S, EoCys, Larkspur, and Soltego (board member). The Gray lab receives or has received research funding from Novartis, Takeda, Astellas, Taiho, Jansen, Kinogen, Arbella, Deerfield, and Sanofi. All other authors do not have any competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)
- Published
- 2021
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