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Taxane-induced attenuation of the CXCR2/BCL-2 axis aensitizes prostate cancer to platinum-based treatment

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dc.contributor.author Ruiz de Porras, Vicenç
dc.contributor.author Indacochea Cusirramos, Alberto
dc.contributor.author Aytes, Alvaro
dc.date.accessioned 2020-12-16T07:12:12Z
dc.date.available 2020-12-16T07:12:12Z
dc.date.issued 2020
dc.identifier.citation Ruiz de Porras V, X Wang XC, Palomero L, Marin-Aguilera M, Solé-Blanch C, Indacochea A et al. Taxane-induced attenuation of the CXCR2/BCL-2 axis aensitizes prostate cancer to platinum-based treatment. Eur Urol. 2020 Nov 2;79(6):722-33. DOI: 10.1016/j.eururo.2020.10.001
dc.identifier.issn 0302-2838
dc.identifier.uri http://hdl.handle.net/10230/46060
dc.description.abstract Background: Taxanes are the most active chemotherapy agents in metastatic castration-resistant prostate cancer (mCRPC) patients; yet, resistance occurs almost invariably, representing an important clinical challenge. Taxane-platinum combinations have shown clinical benefit in a subset of patients, but the mechanistic basis and biomarkers remain elusive. Objective: To identify mechanisms and response indicators for the antitumor efficacy of taxane-platinum combinations in mCRPC. Design, setting, and participants: Transcriptomic data from a publicly available mCRPC dataset of taxane-exposed and taxane-naïve patients were analyzed to identify response indicators and emerging vulnerabilities. Functional and preclinical validation was performed in taxane-resistant mCRPC cell lines and genetically engineered mouse models (GEMMs). Intervention: Metastatic CRPC cells were treated with docetaxel, cisplatin, carboplatin, the CXCR2 antagonist SB265610, and the BCL-2 inhibitor venetoclax. Gain and loss of function in culture of CXCR2 and BCL-2 were achieved by overexpression or siRNA silencing. Preclinical assays in GEMM mice tested the antitumor efficacy of taxane-platinum combinations. Outcome measurements and statistical analysis: Proliferation, apoptosis, and colony assays measured drug activity in vitro. Preclinical endpoints in mice included growth, survival, and histopathology. Changes in CXCR2, BCL-2, and chemokines were analyzed by reverse transcriptase quantitative polymerase chain reaction and Western blot. Human expression data were analyzed using Gene Set Enrichment Analysis, hierarchical clustering, and correlation studies. GraphPad Prism software and R-studio were used for statistical and data analyses. Results and limitations: Transcriptomic data from taxane-exposed human mCRPC tumors correlate with a marked negative enrichment of apoptosis and inflammatory response pathways accompanied by a marked downregulation of CXCR2 and BCL-2. Mechanistically, we show that docetaxel inhibits CXCR2 and that BCL-2 downregulation occurs as a downstream effect. Further, we demonstrated in experimental models that the sensitivity to cisplatin is dependent on CXCR2 and BCL-2, and that targeting them sensitizes prostate cancer (PC) cells to cisplatin. In vivo taxane-platinum combinations are highly synergistic, and previous exposure to taxanes sensitizes mCRPC tumors to second-line cisplatin treatment. Conclusions: The hitherto unappreciated attenuation of the CXCR2/BCL-2 axis in taxane-treated mCRPC patients is an acquired vulnerability with potential predictive activity for platinum-based treatments. Patient summary: A subset of patients with aggressive and therapy-resistant prostate cancer benefits from taxane-platinum combination chemotherapy; however, we lack the mechanistic understanding of how that synergistic effect occurs. Here, using patient data and preclinical models, we found that taxanes reduce cancer cell escape mechanisms to chemotherapy-induced cell death, hence making these cells more vulnerable to additional platinum treatment.
dc.description.sponsorship This work was supported by funding from the “Badalona Foundation Against Cancer” grant (Albert Font) and from Instituto de Salut Carlos III (PI16/01070 and CP15/00090; Alvaro Aytes), the European Association of Urology Research Foundation (EAURF/407003/XH; Alvaro Aytes),Fundacion BBVA (Alvaro Aytes), Department of Defense Award (W81XWH-18-1-0193; Alvaro Aytes), the CERCA Program/Generalitat de Catalunya (Alvaro Aytes), and FEDER funds/European Regional Development Fund (ERDF)—a way to Build Europe (Alvaro Aytes)
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Elsevier
dc.relation.ispartof European Urology. 2020 Nov 2;79(6):722-33
dc.rights © 2020 Vicenç Ruiz de Porras et al. Published by Elsevier B.V. on behalf of European Association of Urology. This article is available under the Creative Commons CC-BY-NC-ND license and permits non-commercial use of the work as published, without adaptation or alteration provided the work is fully attributed
dc.rights.uri https://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject.other Pròstata -- Càncer
dc.subject.other Quimioteràpia
dc.title Taxane-induced attenuation of the CXCR2/BCL-2 axis aensitizes prostate cancer to platinum-based treatment
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1016/j.eururo.2020.10.001
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion


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