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

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

  • Eur Urol. 2021 Jun;79(6):722-733. doi: 10.1016/j.eururo.2020.10.001.
Vicenç Ruiz de Porras 1,  Xieng C Wang 2,  Luis Palomero 2,  Mercedes Marin-Aguilera 3,  Carme Solé-Blanch 1,  Alberto Indacochea 4,  Natalia Jimenez 3,  Sara Bystrup 5,  Martin Bakht 6,  Vincenza Conteduca 7,  Josep M Piulats 8,  Oscar Buisan 9,  José F Suarez 10,  Juan Carlos Pardo 11,  Elena Castro 12,  David Olmos 12,  Himisha Beltran 6,  Begoña Mellado 13,  Eva Martinez-Balibrea 5,  Albert Font 14,  Alvaro Aytes 15
Affiliations

Affiliations

  • 1 Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain; Catalan Institute of Oncology, Badalona Applied Research Group in Oncology (B·ARGO), Badalona, Spain.
  • 2 Program of Molecular Mechanisms and Experimental Therapeutics in Oncology, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet de Llobregat, Gran Via de L'Hospitalet, Barcelona, Spain.
  • 3 Translational Genomics and Targeted Therapeutics in Solid Tumors Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
  • 4 Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain.
  • 5 Germans Trias i Pujol Research Institute (IGTP), Badalona, Spain; Program Against Cancer Therapeutics Resistance (ProCURE), Catalan Institute of Oncology, Gran Via de L'Hospitalet, Barcelona, Spain.
  • 6 Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.
  • 7 Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA; Instituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), IRCCS, Meldola, Italy.
  • 8 Program of Molecular Mechanisms and Experimental Therapeutics in Oncology, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet de Llobregat, Gran Via de L'Hospitalet, Barcelona, Spain; Department of Medical Oncology, Catalan Institute of Oncology (ICO), Hospitalet de Llobregat, Barcelona, Spain.
  • 9 Department of Urology, Hospital Germans Trias I Pujol, Badalona, Spain.
  • 10 Program of Molecular Mechanisms and Experimental Therapeutics in Oncology, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet de Llobregat, Gran Via de L'Hospitalet, Barcelona, Spain; Department of Urology, Bellvitge University Hospital, Hospitalet de Llobregat, Barcelona, Spain.
  • 11 Catalan Institute of Oncology, Badalona Applied Research Group in Oncology (B·ARGO), Badalona, Spain; Department of Medical Oncology, Catalan Institute of Oncology, Badalona, Spain.
  • 12 Genitourinary Cancer Translational Research Group, The Institute of Biomedical Research in Málaga, Málaga, Spain; Prostate Cancer Clinical Research Unit, Spanish National Cancer Research Centre, Madrid, Spain.
  • 13 Translational Genomics and Targeted Therapeutics in Solid Tumors Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Department of Medical Oncology, Hospital Clínic, Barcelona, Spain.
  • 14 Catalan Institute of Oncology, Badalona Applied Research Group in Oncology (B·ARGO), Badalona, Spain; Department of Medical Oncology, Catalan Institute of Oncology, Badalona, Spain. Electronic address: afont@iconcologia.net.
  • 15 Program of Molecular Mechanisms and Experimental Therapeutics in Oncology, Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet de Llobregat, Gran Via de L'Hospitalet, Barcelona, Spain; Program Against Cancer Therapeutics Resistance (ProCURE), Catalan Institute of Oncology, Gran Via de L'Hospitalet, Barcelona, Spain. Electronic address: aaytes@idibell.cat.
PMID: 33153817 DOI: 10.1016/j.eururo.2020.10.001
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.

Keywords

Combination treatment; Metastatic castration-resistant prostate cancer; Platinum; Taxane resistance.

Figures
Products