Trop2 is a driver of metastatic prostate cancer with neuroendocrine phenotype via PARP1
Menée in vitro et à l'aide d'un modèle murin, cette étude met en évidence un mécanisme par lequel la glycoprotéine transmembranaire Trop2 favorise, par l'intermédiaire de la glycosyl-transférase PARP1, le développement d'un cancer métastatique de la prostate de type neuroendocrine
NEPC is a highly aggressive subtype of prostate cancer that is increasing in incidence, likely due to use of new secondary androgen deprivation therapies. Here, we demonstrate that Trop2 is significantly elevated in CRPC and NEPC and represents a driver of metastatic NEPC. Trop2 overexpression increases tumor growth, drives metastasis and neuroendocrine phenotype, and significantly increases PARP1 levels. Inhibition of PARP1 in Trop2-driven NEPC significantly decreases neuroendocrine features, tumor growth, and metastatic colonization in vivo, suggesting that PARP1 inhibitors may represent a promising therapeutic strategy for metastatic prostate cancer expressing high levels of Trop2.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.