Journal Article

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

Zhang, Chiyuan Amy, Kumar, Sahil, Gambhir, Sanjiv S., Kunder, Christian A., Zoubeidi, Amina, Stoyanova, Tanya, Hsu, En-Chi, Zlitni, Aimen, Pitteri, Sharon J., Aslan, Merve, Bermudez, Abel, Chen, Yun-Sheng, Nolley, Rosalie, Habte, Frezghi, Rice, Meghan A., Marques, Fernando Jose Garcia, Peehl, Donna M., Koul, Kashyap, Liu, Shiqin, Ghoochani, Ali, Shen, Michelle, Brooks, James D.

2020

Overview

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.

• Publisher: National Academy of Sciences
• Subject: Animals / Antigens, Neoplasm - genetics / Antigens, Neoplasm - metabolism / Apoptosis / Biological Sciences / Biomarkers, Tumor - genetics / Biomarkers, Tumor - metabolism / Bone Neoplasms - drug therapy / Bone Neoplasms - metabolism / Bone Neoplasms - secondary / Carcinoma, Neuroendocrine - drug therapy / Carcinoma, Neuroendocrine - metabolism / Carcinoma, Neuroendocrine - pathology / Castration / Cell Adhesion Molecules - genetics / Cell Adhesion Molecules - metabolism / Cell Biology / Cell Movement / Cell Proliferation / Cell surface / Colonization / Deprivation / Follow-Up Studies / Gene Expression Regulation, Neoplastic / Genotype & phenotype / Humans / Male / Metastases / Metastasis / Mice / Mice, Inbred NOD / Mice, SCID / Neoplasm Invasiveness / Phenotype / Phenotypes / PNAS Plus / Poly (ADP-Ribose) Polymerase-1 - antagonists & inhibitors / Poly (ADP-Ribose) Polymerase-1 - genetics / Poly (ADP-Ribose) Polymerase-1 - metabolism / Poly(ADP-ribose) polymerase / Poly(ADP-ribose) Polymerase Inhibitors - pharmacology / Prognosis / Prostate cancer / Prostatic Neoplasms, Castration-Resistant - drug therapy / Prostatic Neoplasms, Castration-Resistant - metabolism / Prostatic Neoplasms, Castration-Resistant - pathology / Survival Rate / Therapeutic applications / Tumor Cells, Cultured / Tumors / Xenograft Model Antitumor Assays