AUTHOR=Ghallab Alaa M. , Eissa Reda A. , El Tayebi Hend M. 

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

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.862125

DOI=10.3389/fphar.2022.862125

ISSN=1663-9812

ABSTRACT=Triple negative breast cancer (TNBC) is the most malignant subtype of breast cancer as the absence of cell surface receptors renders it more difficult to be therapeutically targeted. Chemokine receptor 2 (CXCR2) has been suggested not only to promote therapy resistance and suppress immunotherapy but it is also known to possess a positive cross talk with the multifunctional cytokine transforming growth factor beta (TGF‐β). Here we showed that CXCR2 and TGF‐ β signaling were both upregulated in human TNBC biopsies. CXCR2 inhibition abrogated Doxorubicin‐mediated TGF‐ β upregulation in 3D ex vivo TNBC culture and eliminated the drug resistance in TNBC mammospheres, suggesting a vital role for CXCR2 in TNBC Doxorubicin-resistance via TGFβ signaling regulation. Moreover, CXCR2 inhibition improved the efficacy of the immunotherapeutic drug "Atezolizumab" where the combined inhibition of CXCR2 and PDL-1 in TNBC ex vivo culture showed an additive effect in cytotoxicity. Altogether, the current study suggests CXCR2 inhibitors as a promising approach to improve TNBC treatment if used in combination with chemotherapy and/or immunotherapy.