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Targeting Pin1 renders pancreatic cancer eradicable by synergizing with immunochemotherapy.
Koikawa, Kazuhiro; Kibe, Shin; Suizu, Futoshi; Sekino, Nobufumi; Kim, Nami; Manz, Theresa D; Pinch, Benika J; Akshinthala, Dipikaa; Verma, Ana; Gaglia, Giorgio; Nezu, Yutaka; Ke, Shizhong; Qiu, Chenxi; Ohuchida, Kenoki; Oda, Yoshinao; Lee, Tae Ho; Wegiel, Babara; Clohessy, John G; London, Nir; Santagata, Sandro; Wulf, Gerburg M; Hidalgo, Manuel; Muthuswamy, Senthil K; Nakamura, Masafumi; Gray, Nathanael S; Zhou, Xiao Zhen; Lu, Kun Ping.
Afiliação
  • Koikawa K; Division 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, H
  • Kibe S; Division 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, H
  • Suizu F; Division 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, H
  • Sekino N; Division 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, H
  • Kim N; Division 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, H
  • Manz TD; Department 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.
  • Pinch BJ; Department 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.
  • Akshinthala D; 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.
  • Verma A; Ludwig 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.
  • Gaglia G; Ludwig 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.
  • Nezu Y; Division 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, H
  • Ke S; Division 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, H
  • Qiu C; Division 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, H
  • Ohuchida K; Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
  • Oda Y; Department of Anatomical Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
  • Lee TH; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
  • Wegiel B; Cancer 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 Med
  • Clohessy JG; Cancer 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.
  • London N; Department of Chemical and Structural Biology, The Weizmann Institute of Science, Rehovot, 7610001, Israel.
  • Santagata S; Ludwig 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.
  • Wulf GM; 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.
  • Hidalgo M; 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.
  • Muthuswamy SK; 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.
  • Nakamura M; Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
  • Gray NS; Department of Chemical and Systems Biology, Chem-H and Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA.
  • Zhou XZ; Division 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, H
  • Lu KP; Division 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, H
Cell ; 184(18): 4753-4771.e27, 2021 09 02.
Article em En | MEDLINE | ID: mdl-34388391
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.
Assuntos
Imunoterapia; Terapia de Alvo Molecular; Peptidilprolil Isomerase de Interação com NIMA/metabolismo; Neoplasias Pancreáticas/tratamento farmacológico; Neoplasias Pancreáticas/imunologia; Proteínas Adaptadoras de Transdução de Sinal/química; Proteínas Adaptadoras de Transdução de Sinal/metabolismo; Adenocarcinoma/tratamento farmacológico; Adenocarcinoma/imunologia; Adenocarcinoma/patologia; Aloenxertos/imunologia; Motivos de Aminoácidos; Animais; Apoptose/efeitos dos fármacos; Antígeno B7-H1/metabolismo; Fibroblastos Associados a Câncer/metabolismo; Fibroblastos Associados a Câncer/patologia; Carcinoma Ductal Pancreático/tratamento farmacológico; Carcinoma Ductal Pancreático/imunologia; Carcinoma Ductal Pancreático/patologia; Linhagem Celular Tumoral; Membrana Celular/efeitos dos fármacos; Membrana Celular/metabolismo; Desoxicitidina/análogos & derivados; Desoxicitidina/farmacologia; Desoxicitidina/uso terapêutico; Sinergismo Farmacológico; Endocitose/efeitos dos fármacos; Transportador Equilibrativo 1 de Nucleosídeo/metabolismo; Humanos; Terapia de Imunossupressão; Lisossomos/efeitos dos fármacos; Lisossomos/metabolismo; Camundongos; Proteínas dos Microfilamentos/química; Proteínas dos Microfilamentos/metabolismo; Oncogenes; Organoides/efeitos dos fármacos; Organoides/patologia; Transdução de Sinais/efeitos dos fármacos; Análise de Sobrevida; Microambiente Tumoral/efeitos dos fármacos; Ensaios Antitumorais Modelo de Xenoenxerto; Gencitabina
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Pancreáticas / Terapia de Alvo Molecular / Peptidilprolil Isomerase de Interação com NIMA / Imunoterapia Idioma: En Revista: Cell Ano de publicação: 2021 Tipo de documento: Article
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Pancreáticas / Terapia de Alvo Molecular / Peptidilprolil Isomerase de Interação com NIMA / Imunoterapia Idioma: En Revista: Cell Ano de publicação: 2021 Tipo de documento: Article