ArticleCell2021
Targeting Pin1 renders pancreatic cancer eradicable by synergizing with immunochemotherapy.
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Article in Cell, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 140 papers.
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140citing papers in PubMed
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140 citing papers in PubMed, 233 citations in OpenAlex.
- Propionyl-CoA catabolism is a metabolic gatekeeper for fatty acid oxidation in pancreatic cancer.Oncogene · 2026Article
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- Article
- CAF-derived PAI-1 serves as an EGFR ligand and fuels KRAS-mutant pancreatic cancer.Nature communications · 2026Article
- Targeting CD3L1-NRP2 disarms myeloid-driven tumor immune evasion.EMBO molecular medicine · 2026Article
- The Evolving Landscape of Immune Regulation and Immunotherapy in Cholangiocarcinoma and Biliary Tract Cancer.Cancers · 2026Review
- Review
- Systematic Optimization of Proteolysis-Targeting Chimeras for PIN1 Enables Selective Degradation and Antitumor Activity In Vivo.Pharmaceutics · 2026Article
- Natural bioactive molecules and chemotherapeutics synergism for enhanced cancer therapy.Nutrition & metabolism · 2026Review
- A comprehensive review of mechanisms underlying resistance to immune checkpoint inhibitors.Frontiers in immunology · 2026Review
- Enteric neuro-immune-tumor ecosystem in pancreatic, colorectal, and gastric malignancies: context dependence and translational priorities.Frontiers in immunology · 2026Review
- KRAS-driven cytokine-metabolic crosstalk shapes immune exclusion in pancreatic ductal adenocarcinoma.Frontiers in genetics · 2026Review
- Scaffold Hopping and Optimization of Thiazole Hybrids as Selective PIN1 Inhibitors: A Computational Study.Medicinal chemistry (Shariqah (United Arab Emirates)) · 2026Article
- Pre-clinical evaluation of a potent and effective Pin1-degrading agent in pancreatic cancer.Molecular therapy. Oncology · 2025Article
- A computational analysis of programmed cell death-associated LncRNA signatures in glioma and drug prediction.BMC neurology · 2025Article
- The Prolyl Isomerase PIN1 Affects Fibroblast Differentiation States and Cross-talk in Pancreatic Cancer.Cancer research · 2025Article
- Patient-Derived Organoids as a Platform to Decipher and Overcome Radioresistance: From the Tumor Microenvironment to Radiosensitizer Discovery.Current oncology (Toronto, Ont.) · 2025Review
- Bibliometric analysis of global research trends in pancreatic cancer immunotherapy.Human vaccines & immunotherapeutics · 2025Article
- Engineering a spatiotemporal macrophage circuit via STING phase separation to override immune suppression in pancreatic cancer.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Ginsenoside Rh2 as a novel PIN1 inhibitor disrupting the cancer stem cell-like phenotype in non-small cell lung cancer.Journal of translational medicine · 2025Article
80 more citing papers are in PubMed but not listed here.
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Authors and funding
27 authors at 7 institutions in 3 countries.
Kazuhiro KoikawaDivision of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA; Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Shin KibeDivision of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA; Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan; Chemical Biology and Therapeutics Science Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Futoshi SuizuDivision of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA; Division of Cancer Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo 060-0815, Japan.
Nobufumi SekinoDivision of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA; Chemical Biology and Therapeutics Science Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Nami KimDivision of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Theresa D ManzDepartment of Cancer Biology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Benika J PinchDepartment of Cancer Biology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Dipikaa AkshinthalaDepartment of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Ana VermaLudwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA; Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Giorgio GagliaLudwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA; Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Yutaka NezuDivision of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA.
Shizhong KeDivision of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA; Chemical Biology and Therapeutics Science Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Chenxi QiuDivision of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA; Chemical Biology and Therapeutics Science Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Kenoki OhuchidaDepartment of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Yoshinao OdaDepartment of Anatomical Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Tae Ho LeeDepartment of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Babara WegielCancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Division of Surgical Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
John G ClohessyCancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Preclinical Murine Pharmacogenetics Facility, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Nir LondonDepartment of Chemical and Structural Biology, The Weizmann Institute of Science, Rehovot, 7610001, Israel.
Sandro SantagataLudwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA; Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Gerburg M WulfDepartment of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Manuel HidalgoDepartment of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Senthil K MuthuswamyDepartment of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Masafumi NakamuraDepartment of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
Nathanael S GrayDepartment of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA.
Xiao Zhen ZhouDivision of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA; Chemical Biology and Therapeutics Science Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: xzhouenator@gmail.com.
Kun Ping LuDivision of Translational Therapeutics, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA; Chemical Biology and Therapeutics Science Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: klu@broadinstitute.org.
Beth Israel Deaconess Medical Center · USBroad Institute · USBrigham and Women's Hospital · USKyushu University · JPHarvard University · USStanford University · USWeizmann Institute of Science · IL
Funding
UNC-CH CENTER FOR ENVIRONMENTAL HEALTH &SUSCEPTIBILITYP30ES010126 · NIEHS · UNIV OF NORTH CAROLINA CHAPEL HILL · PI Stephanie Engel · 2001 to 2026
$36.3MTissue and Pathology CoreP50CA168504 · NCI · DANA-FARBER CANCER INST · PI Nabihah Tayob · 2013 to 2026
$30.1MVASCULAR, PULMONARY AND RENAL INJURYT32HL007627 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI GIMBRONE, MICHAEL A, MITCHELL, RICHARD N · 1985 to 2019
$12.7MSystems Pharmacology of Therapeutic and Adverse Responses to ImmuneCheckpoint and Small Molecule DrugsU54CA225088 · NCI · HARVARD MEDICAL SCHOOL · PI LATORRE, ISABEL · 2018 to 2022
$10.8MATP-Dependent Chromatin Remodeling in Human MalignancyR01CA163915 · NCI · STANFORD UNIVERSITY · PI Gerald R. Crabtree · 2012 to 2026
$5.4MDevelopment of Therapeutic Antibody for Traumatic Brain InjuryU01NS096835 · NINDS · BETH ISRAEL DEACONESS MEDICAL CENTER · PI ZEIDEL, MARK L. · 2017 to 2021
$5.1MRole of Tau Conformations in Vascular Contribution to Cognitive Impairment and DementiaR01AG055559 · NIA · BETH ISRAEL DEACONESS MEDICAL CENTER · PI LO, ENG H., SHEHADAH, AMJAD · 2017 to 2021
$3.4MStopping PDA progression using inhibitors of CSC dissemination and immunotherapyU01CA224193 · NCI · FRED HUTCHINSON CANCER RESEARCH CENTER · PI HINGORANI, SUNIL R · 2017 to 2021
$3.3MDevelopment of selective Pin1 inhibitors to target a common oncogenic mechanismR01CA205153 · NCI · BETH ISRAEL DEACONESS MEDICAL CENTER · PI GRAY, NATHANAEL SCHIANDER, WULF, GERBURG M · 2017 to 2021
$3.3MHIJACKING CANCER DRIVERS TO ACTIVATE PROAPOPTOTIC GENES IN DLBCLR01CA276167 · NCI · STANFORD UNIVERSITY · PI Gerald R. Crabtree, NATHANAEL Schiander GRAY · 2023 to 2026
$2.2MOptimization of PI3K-inhibitors to augment the efficacy of microtubule-disrupting chemotherapyR01CA226776 · NCI · BETH ISRAEL DEACONESS MEDICAL CENTER · PI WULF, GERBURG M · 2018 to 2022
$2.1MNCI NIH HHS P50 CA168504NCI NIH HHS R01 CA163915NCI NIH HHS R01 CA205153NCI NIH HHS R01 CA226776NCI NIH HHS R01 CA276167NCI NIH HHS U01 CA224193NCI NIH HHS U54 CA225088NHLBI NIH HHS T32 HL007627NIA NIH HHS R01 AG055559NINDS NIH HHS U01 NS096835
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.
Indexed as
ImmunotherapyMolecular Targeted TherapyAdaptor Proteins, Signal TransducingAdenocarcinomaAllograftsAmino Acid MotifsAnimalsApoptosisB7-H1 AntigenCancer-Associated FibroblastsCarcinoma, Pancreatic DuctalCell Line, TumorCell MembraneDeoxycytidineDrug SynergismEndocytosisAdaptor Proteins, Signal TransducingB7-H1 AntigenCD274 protein, humanDeoxycytidineEquilibrative Nucleoside Transporter 1GemcitabineHIP1R protein, humanMicrofilament ProteinsNIMA-Interacting Peptidylprolyl IsomerasePin1 protein, mouseSLC29A1 protein, humancancer-associated fibroblastscancer immune evasionchemotherapycombination therapyimmuni checkpoint therapypancreatic cancerPin1targeted therapytumor immune microenvironmenttumor microenvironment
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