CDCP1 overexpression drives prostate cancer progression and can be targeted in vivo
Abdullah Alajati, … , Johann De Bono, Andrea Alimonti
Abdullah Alajati, … , Johann De Bono, Andrea Alimonti
Published April 6, 2020
Citation Information: J Clin Invest. 2020;130(5):2435-2450. https://doi.org/10.1172/JCI131133.
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Research Article Oncology

CDCP1 overexpression drives prostate cancer progression and can be targeted in vivo

Abstract

The mechanisms by which prostate cancer shifts from an indolent castration-sensitive phenotype to lethal castration-resistant prostate cancer (CRPC) are poorly understood. Identification of clinically relevant genetic alterations leading to CRPC may reveal potential vulnerabilities for cancer therapy. Here we find that CUB domain-containing protein 1 (CDCP1), a transmembrane protein that acts as a substrate for SRC family kinases (SFKs), is overexpressed in a subset of CRPC. Notably, CDCP1 cooperates with the loss of the tumor suppressor gene PTEN to promote the emergence of metastatic prostate cancer. Mechanistically, we find that androgens suppress CDCP1 expression and that androgen deprivation in combination with loss of PTEN promotes the upregulation of CDCP1 and the subsequent activation of the SRC/MAPK pathway. Moreover, we demonstrate that anti-CDCP1 immunoliposomes (anti–CDCP1 ILs) loaded with chemotherapy suppress prostate cancer growth when administered in combination with enzalutamide. Thus, our study identifies CDCP1 as a powerful driver of prostate cancer progression and uncovers different potential therapeutic strategies for the treatment of metastatic prostate tumors.

Authors

Abdullah Alajati, Mariantonietta D’Ambrosio, Martina Troiani, Simone Mosole, Laura Pellegrini, Jingjing Chen, Ajinkya Revandkar, Marco Bolis, Jean-Philippe Theurillat, Ilaria Guccini, Marco Losa, Arianna Calcinotto, Gaston De Bernardis, Emiliano Pasquini, Rocco D’Antuono, Adam Sharp, Ines Figueiredo, Daniel Nava Rodrigues, Jonathan Welti, Veronica Gil, Wei Yuan, Tatjana Vlajnic, Lukas Bubendorf, Giovanna Chiorino, Letizia Gnetti, Verónica Torrano, Arkaitz Carracedo, Laura Camplese, Susumu Hirabayashi, Elena Canato, Gianfranco Pasut, Monica Montopoli, Jan Hendrik Rüschoff, Peter Wild, Holger Moch, Johann De Bono, Andrea Alimonti

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Figure 6

CDCP1 targeting improves the efficacy of ADTs.

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CDCP1 targeting improves the efficacy of ADTs. (A) Quantification of fol...
(A) Quantification of fold change in growth by crystal violet in LNCaP cell line untreated and treated with enzalutamide (10 μM) in combination with or without the immune-liposome (anti–CDCP1-ILs). Enzalutamide (10 μM) treatment lasted for 26 days. After that, cells were treated in combination with anti–CDCP1-ILs. (B) Quantification of cell death with 7-AAD staining in cells untreated and treated with enzalutamide in combination with or without the anti–CDCP1-ILs (n = 4). (C) Xenografts tumor growth (mm3) of LNCaP cell line untreated or treated with enzalutamide in the presence or absence of the anti–CDCP1-ILs. Upon tumor establishment, mice were treated with enzalutamide (10 mg/kg) for 45 days. After the first week of enzalutamide treatments, mice were divided into 2 groups and treated with or without the anti–CDCP1-ILs. Note that the 2 treatments were consecutive (n = 4). (D) The model represents the role of CDCP1 in CRPC. PI3K partially blocks AR. ADT blocks AR completely and upregulates CDCP1 levels. Error bars indicate SD for B and SEM for C. ***P < 0.001; ****P < 0.0001. The following statistical test was used: 1-way ANOVA adjusted for multiple comparisons using Tukey’s test.