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CXCR2 Small-Molecule Antagonist Combats Chemoresistance and Enhances Immunotherapy in Triple-Negative Breast Cancer

Alaa M Ghallab1, Reda A Eissa2, Hend M El Tayebi1

  • 1The Molecular Pharmacology Research Group, Department of Pharmacology, Toxicology and Clinical Pharmacy, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt.

Frontiers in Pharmacology
|May 6, 2022
PubMed

Insights

Targeting chemokine receptor 2 (CXCR2) may overcome triple-negative breast cancer (TNBC) resistance to chemotherapy and immunotherapy. Inhibiting CXCR2 reduces drug resistance and enhances anti-cancer immune responses, offering a promising therapeutic strategy for TNBC.

Area of Science:

  • Oncology
  • Immunology
  • Pharmacology

Background:

  • Triple-negative breast cancer (TNBC) is aggressive and difficult to treat due to a lack of targeted therapies.
  • Chemokine receptor 2 (CXCR2) signaling is implicated in therapy resistance and immune suppression in TNBC.
  • CXCR2 interacts with transforming growth factor beta (TGF-β), a cytokine involved in cancer progression.

Purpose of the Study:

  • To investigate the role of CXCR2 and TGF-β signaling in TNBC.
  • To evaluate the efficacy of CXCR2 inhibition in overcoming chemoresistance and enhancing immunotherapy in TNBC models.

Main Methods:

  • Analysis of CXCR2 and TGF-β expression in human TNBC biopsies.
  • In vitro studies using 3D TNBC cocultures with PBMCs and TNBC mammospheres.
  • Assessment of doxorubicin resistance and response to atezolizumab (anti-PDL1 immunotherapy) following CXCR2 inhibition.

Main Results:

  • CXCR2 and TGF-β signaling were upregulated in human TNBC tissues.
  • CXCR2 inhibition reversed doxorubicin-induced TGF-β upregulation and eliminated drug resistance in TNBC models.
  • Combined inhibition of CXCR2 and PD-L1 demonstrated an additive cytotoxic effect in vitro.

Conclusions:

  • CXCR2 plays a critical role in mediating doxorubicin resistance in TNBC through TGF-β signaling.
  • CXCR2 inhibition can enhance the efficacy of chemotherapy and immunotherapy in TNBC.
  • CXCR2 inhibitors represent a potential therapeutic strategy for improving outcomes in triple-negative breast cancer.
Keywords:
AZD5069CXCR2 inhibitionatezolizumabchemoresistancedoxorubicintriple-negative breast cancer

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