Intrinsic 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 resistant or readily adaptive to therapy. To investigate how transcriptomic heterogeneity influences response and adaptation to targeted therapy in TNBC, this study leverages the ClonMapper cell barcoding system 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. Survival during drug exposure is then modeled as a combination of (1) each subpopulation’s transcriptomic state prior to treatment and (2) persistent gene expression changes occurring during treatment, providing an approach for distinguishing between intrinsic and acquired transcriptional programs associated with heterogeneous response to targeted therapy. This work demonstrates that non-genetic heterogeneity is an important contributor to response and resistance to a set of targeted molecular therapies, highlighting the importance of considering population heterogeneity when studying therapeutic response in TNBC.