Abstract 1334: CCR5 inhibitors enhance doxorubicin-induced breast cancer cell killing while reducing cardiotoxicity

Abstract

Abstract Cardiac toxicity from chemotherapy, which contributes substantially to morbidity and mortality in cancer survivors is dose-dependent, but sensitivity can vary greatly between patients. Doxorubicin (DOX) reduces ventricular ejection fraction to <50% (severe cardiotoxicity) in 9% (250 mg/m2), 18% (350 mg/m2) and 38% (450 mg/m2) of patients. With currently >1.5 million women develop breast cancer annually, it is estimated that >50,000 women/year will develop severe cardiotoxicity. With cancer survivors estimated at 19 million in the USA by 2025, DOX-induced cardiotoxicity is considered part of the “cardio-oncology epidemic”. Two cellular activities: DNA damage, causing double-strand breaks (DSBs) following poisoning of topoisomerase II (Topo II), and chromatin damage, mediated through histone eviction, are required for cardiotoxicity. The only FDA approved preventive, dexrazoxane reduces the anti-cancer efficacy of the DOX-based chemotherapeutic agents has the concerning side effects of myelotoxicity and a possible increased prevalence of secondary malignancies. We previously showed that the G-protein coupled receptor CCR5 is expressed on both immune and epithelial cells of ~50% of human breast cancers (BCa), thereby inducing cancer “stemness”, cell survival and DNA repair and a pro-metastatic phenotype. Moreover, CCR5 expression is enhanced in DOX-resistant BCa cells and CCR5 inhibitors (CCR5i) enhance DOX-induced cell death of BCa cells. Whilst expression of CCR5 and its ligands (CCL3 and CCL5) were induced by DOX-treatment in cardiac myocytes in both a murine model of DOX-cardiac toxicity and in the hearts of patients undergoing cardiac transplantation for DOX-induced cardiomyopathy. Unlike in BCa cells (where the enhanced CCR5 expression is transcriptionaly regulated) the increased expression in the myocardium occurs in the absence of altered mRNA levels suggesting epigenetic control over CCR5 expression during DOX-induced cardiotoxicity. In the myocardium CCR5 signaling promotes cardiac remodeling and heart failure, opposite that in BCa where CCR5 signaling promotes survival. Not surprisingly, CCR5i protected human iPSC-derived cardiomyocytes and isolated canine cardiomyocytes from DOX-induced cell death using nuclear fragmentation (hypodiploid peak) and mitochondrial function (MitoGlo reagent) as endpoints. Further, in a murine model of DOX cardiotoxicity (3 mg/kgx8 doses over 2 weeks) CCR5i substantially reduced (>90%) DOX-induced cardiac dysfunction and mortality in mice. CCR5 inhibitors (CCR5i) are “dual function” compounds that provide both cardiac protection and enhanced breast cancer cell killing in the presence of DNA damaging chemotherapy agents. Our studies may have a broad impact by identifying a novel approach to both enhancing therapeutic efficacy and providing cardioprotection from DNA damaging agents that are widely used in cancer treatment. Citation Format: Anthony W. Ashton, Xuanmao Jiao, Zhiping Li, Joseph C. Wu, Cristobal dos Remedios, Sean Lal, Richard Kitsis, Richard G. Pestell. CCR5 inhibitors enhance doxorubicin-induced breast cancer cell killing while reducing cardiotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1334.