Taxane-induced Attenuation of the CXCR2/BCL-2 Axis Sensitizes Prostate Cancer to Platinum-based Treatment

Autor: Albert Font, David Olmos, Martin Bakht, Sara Bystrup, José Francisco Suárez, Alberto Indacochea, Carme Sole-Blanch, Eva Martinez-Balibrea, Luis Palomero, Alvaro Aytes, Natalia Jiménez, Himisha Beltran, Mercedes Marín-Aguilera, Elena Castro, Vicenç Ruiz de Porras, Josep M. Piulats, Oscar Buisan, Juan Carlos Pardo, Begoña Mellado, Xieng C. Wang, Vincenza Conteduca
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: Università degli studi di Foggia-IRIS
European Urology
r-IGTP. Repositorio Institucional de Producción Científica del Instituto de Investigación Germans Trias i Pujol
instname
Dipòsit Digital de la UB
Universidad de Barcelona
ISSN: 0302-2838
Popis: 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. 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)
Databáze: OpenAIRE
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