1. Targeting Pin1 renders pancreatic cancer eradicable by synergizing with immunochemotherapy
- Author
-
Sandro Santagata, Nathanael S. Gray, Theresa D. Manz, Nami Kim, Nobufumi Sekino, Xiao Zhen Zhou, Futoshi Suizu, Giorgio Gaglia, Dipikaa Akshinthala, Shizhong Ke, Benika J. Pinch, Manuel Hidalgo, Babara Wegiel, Kun Ping Lu, Senthil K. Muthuswamy, Yutaka Nezu, Kenoki Ohuchida, Shin Kibe, Gerburg M. Wulf, Chenxi Qiu, Nir London, Tae Ho Lee, Yoshinao Oda, Ana Verma, Kazuhiro Koikawa, John G. Clohessy, and Masafumi Nakamura
- Subjects
Tumor microenvironment ,Combination therapy ,medicine.medical_treatment ,Biology ,medicine.disease ,General Biochemistry, Genetics and Molecular Biology ,Gemcitabine ,Targeted therapy ,Cancer immunotherapy ,Pancreatic cancer ,Cancer cell ,medicine ,Cancer research ,Cancer-Associated Fibroblasts ,medicine.drug - 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.
- Published
- 2021
- Full Text
- View/download PDF