Innate and Acquired Transcriptional Programs Shape Heterogeneous Tumor Cell Responses to PARP, Akt, and CDK4/6 Inhibitors

Targeted therapies are increasingly utilized across cancer types, yet their efficacy in triple-negative breast cancer (TNBC) remains limited due to the disease’s high heterogeneity and aggressive nature. In a heterogeneous tumor, treatment failure can occur due to the presence of therapy-tolerant cells, which may either be innately drug-tolerant or readily adaptive to therapy cytotoxicity. To investigate how transcriptomic heterogeneity influences response and adaptation to targeted therapy in TNBC, this study leverages the ClonMapper cell barcoding system combined with single-cell RNA sequencing (scRNA-seq) to track differential responses of DNA barcoded clonal subpopulations during treatment with PARP-, Akt-, and CDK4/6-targeting therapy. For the three different targeted therapies, distinct innate and acquired gene signatures, unique to each therapy type, are shown to be predictive of a cell’s level of persistence during treatment. This work demonstrates that non-genetic heterogeneity plays a central role in response and resistance to targeted therapy, highlighting the need to consider tumor heterogeneity to guide effective use of targeted chemotherapy in TNBC.