Topoisomerase I inhibitor antibody–drug conjugates in breast cancer: the relevance of the DNA damage response to resistance, response, and combination treatment strategies

INTRODUCTION: Antibody drug conjugates (ADCs) have revolutionized cancer treatment. ADCs that contain topoisomerase I inhibitors have been especially important in breast cancer treatment. Despite the substantial progress brought about by these ADCs, there remains a critical need to explore combination treatment strategies to overcome resistance and enhance the efficacy of these agents. Topoisomerase I inhibitors induce DNA damage and thus activate the DNA damage response (DDR). DDR elements have been examined in terms of their role in resistance and response to topoisomerase I inhibitors, and DDR inhibitors may be especially powerful when combined with topoisomerase I inhibitors. METHODS: This review will discuss the topoisomerase I inhibitor ADCs approved for breast cancer treatment, the relevance of select components of the DNA damage response to topoisomerase I inhibitor-containing therapies, and combination strategies with inhibitors of DNA damage response, specifically focusing on inhibitors of poly (ADP-ribose) polymerase (PARP) and the ataxia-telangiectasia mutated and Rad3-related (ATR) inhibitor. CONCLUSIONS: The introduction of topoisomerase inhibitors as an ADC payload into breast cancer care has redefined a need to better understand the intricacies of their mechanism of action and tumor methods of escape and resistance, hopefully leading to novel synergistic therapeutic strategies.