Synergistic anti-cancer activity of auranofin with anti-PD-L1 therapy in triple negative breast cancer

Abstract

BackgroundTriple-negative breast cancers (TNBCs) are very aggressive and lethal forms of breast cancer with no effective targeted therapy. TNBCs spontaneously metastasize to distant organs including lungs, bone, and brain. Neo-adjuvant chemotherapies and radiotherapy remains a mainstay of treatment with only 25-30% of TNBC patients responding. Thus, there is an unmet clinical need to develop novel therapeutic strategies for TNBCs.MethodsWe tested the anti-cancer activity of auranofin monotherapy on primary tumor growth and metastasis in vitro and in vivo. Further, using in vitro analysis we conceptualized the PD-L1 dependent resistance against auranofin which we validated in vivo using syngeneic TNBC model.ResultsExpression of the thioredoxin pathway genes is significantly upregulated in TNBC patients compared to non-TNBC patients and correlated with adverse survival outcomes. Treatment with auranofin, an FDA-approved thioredoxin reductase inhibitor caused specific cell death and impaired the growth of TNBC grown as spheroids in 3D culture. Further, auranofin treatment exerted a significant in vivo anti-tumor activity in multiple TNBC models including syngeneic 4T1.2 model, human MDA-MB-231 xenograft, and PDX model by inhibiting thioredoxin redox activity. Auranofin also significantly inhibited the invasion potential of TNBC cells in vitro and significantly inhibited lung metastasis in 4T1.2 syngeneic model in vivo by reducing the expression of various EMT markers. We for the first time showed that auranofin increased CD8 +Ve T-cells tumor infiltration in vivo and upregulated immune checkpoint PD-L1 expression in ERK1/2-MYC-dependent manner. Moreover, combination of auranofin with anti-PD-L1 monoclonal antibody synergistically impaired the growth of 4T1.2 primary tumor.ConclusionsOur data provides a novel therapeutic strategy using auranofin in combination with anti-PD-L1 antibody for TNBCs and warrants further clinical investigation for TNBC patients. Since the success rate of anti-PD-L1 therapy is very low in TNBC patients, our data provides a novel strategy to use auranofin with anti-PD-L1 therapy to that may enhance the efficacy of immune checkpoint therapy in TNBC patients.Legal entity responsible for the studyThe authors.FundingCure Cancer Australia & Can Too Foundation Project grant [ID 1147230] to Prahlad Raninga National Health & Medical Research Council (NH&MRC) Program Grant [ID 1017028] to Kum Kum Khanna Perpetual IMPACT Philanthropy project grant [IPAP201602001] to Kum Kum Khanna and Murugan Kalimutho.DisclosureAll authors have declared no conflicts of interest.