Molecular Framework of T-DXd Acquired Resistance in HER2-Positive Breast Cancer

Abstract

T-DXd has transformed the world of directed treatment of HER2 positive breast cancer but its clinical benefit over an extended period of time is severely constrained by unavoidable acquired resistance. Although recent studies have examined specific resistance pathways, a comprehensive overview of this very heterogeneous molecular network is still relatively absent. The present study systematically examines the stratified biological processes that form the basis of the acquired T-DXd resistance as informed by the pharmacokinetic profiles of antibody drug conjugates (ADCs) and describes in great detail all the components of a full resistance model, including the loss of antigen binding and intracellular metabolic escape mechanisms. Besides, it also shows what leads to severe resistance by the nuclear DNA damage repair compensation mechanism, illustrated by SLX4-deficiency, which clearly defines the essential evolutionary mechanisms used by the tumor cells to avoid ADC-mediated killing. These main insights offer important theoretical direction to clinicians when developing personalized, evidence-based combination therapies in patients who are progressing post-T-DXd resistance. Nevertheless, the absence of empirical verification in the form of massive clinical cohorts in real life has been an unsolved weakness of this discipline. Next-generation research should be aimed at using non-invasive liquid biopsy techniques to observe the clonal evolution in real-time and fast-track the generation of new combination approaches to eliminate the resistance obstacles conclusively.