Trop2 is a driver of metastatic prostate cancer with neuroendocrine phenotype via PARP1.

Abstract

Resistance to androgen deprivation therapy, or castration-resistant prostate cancer (CRPC), is often accompanied by metastasis and is currently the ultimate cause of prostate cancer-associated deaths in men. Recently, secondary hormonal therapies have led to an increase of neuroendocrine prostate cancer (NEPC), a highly aggressive variant of CRPC. Here, we identify that high levels of cell surface receptor Trop2 are predictive of recurrence of localized prostate cancer. Moreover, Trop2 is significantly elevated in CRPC and NEPC, drives prostate cancer growth, and induces neuroendocrine phenotype. Overexpression of Trop2 induces tumor growth and metastasis while loss of Trop2 suppresses these abilities in vivo. Trop2-driven NEPC displays a significant up-regulation of PARP1, and PARP inhibitors significantly delay tumor growth and metastatic colonization and reverse neuroendocrine features in Trop2-driven NEPC. Our findings establish Trop2 as a driver and therapeutic target for metastatic prostate cancer with neuroendocrine phenotype and suggest that high Trop2 levels could identify cancers that are sensitive to Trop2-targeting therapies and PARP1 inhibition.

• Authors: En-Chi Hsu, Meghan A Rice, Abel Bermudez, Fernando Jose Garcia Marques, Merve Aslan, Shiqin Liu, Ali Ghoochani, Chiyuan Amy Zhang, Yun-Sheng Chen, Aimen Zlitni, Sahil Kumar, Rosalie Nolley, Frezghi Habte, Michelle Shen, Kashyap Koul, Donna M Peehl, Amina Zoubeidi, Sanjiv S Gambhir, Christian A Kunder, Sharon J Pitteri, James D Brooks, Tanya Stoyanova
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 117 Issue 4 Pg. 2032-2042 (01 28 2020) ISSN: 1091-6490 [Electronic] United States
• PMID: 31932422 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2020 the Author(s). Published by PNAS.

Chemical References

• Antigens, Neoplasm
• Biomarkers, Tumor
• Cell Adhesion Molecules
• Poly(ADP-ribose) Polymerase Inhibitors
• TACSTD2 protein, human
• PARP1 protein, human
• Poly (ADP-Ribose) Polymerase-1

Topics

• Animals
• Antigens, Neoplasm (genetics, metabolism)
• Apoptosis
• Biomarkers, Tumor (genetics, metabolism)
• Bone Neoplasms (drug therapy, metabolism, secondary)
• Carcinoma, Neuroendocrine (drug therapy, metabolism, pathology)
• Cell Adhesion Molecules (genetics, metabolism)
• Cell Movement
• Cell Proliferation
• Follow-Up Studies
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Neoplasm Invasiveness
• Phenotype
• Poly (ADP-Ribose) Polymerase-1 (antagonists & inhibitors, genetics, metabolism)
• Poly(ADP-ribose) Polymerase Inhibitors (pharmacology)
• Prognosis
• Prostatic Neoplasms, Castration-Resistant (drug therapy, metabolism, pathology)
• Survival Rate
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays