Abstract P3-04-30: Single cell analysis enables tracking the evolution of resistance to CDK4/6 inhibitors in ER+ breast cancer

作者：Yuki Matsunaga, Hima Patel, Emilija Aleksandrovic, Dhyvya R. Sudan, Khushi Ahuja, Dan Ye, Chang-Ching Lin, Lei Guo, X. Cynthia, Siyuan Zhang, Carlos L. Arteaga, Ariella B. Hanker · 发表于：Clinical Cancer Research · 年份：2025 · DOI：10.1158/1557-3265.sabcs24-p3-04-30 · 研究领域：Advanced Breast Cancer Therapies

Abstract The combination of CDK4/6 inhibitors (CDK4/6i) with endocrine therapy prolongs survival of patients with ER+/HER2- metastatic breast cancer. Nearly all patients with advanced disease treated with this combination eventually progress, highlighting a need for therapeutic interventions that prevent the emergence of drug resistance. Drug tolerant persister (DTP) cells represent a reservoir of surviving cells from which drug-resistant clones eventually emerge. We hypothesize that targeting the DTP state which emerges under selective pressure from CDK4/6i could prevent the emergence of drug resistance. In vitro treatment of MCF7 and T47D ER+/HER2- breast cancer cells with the CDK4/6i Palbociclib and estrogen deprivation for 4 weeks suppressed cell viability with 2-5% of cells surviving treatment and achieving a DTP state. Cell cycle analysis by PI staining revealed that 95% of the DTP cells were arrested in G0/G1 after 4 weeks of continuous therapy. Upon drug washout, the DTP population resumed proliferation within ∼1 week and regained sensitivity to retreatment with CDK4/6i, suggesting epigenetic reprogramming is responsible for the DTP state. Whole exome sequencing did not show enrichment of known genomic alterations associated with CDK4/6i resistance (e.g., RB1, FAT1, PTEN). Bulk RNA sequencing of MCF7 DTP cells revealed transcriptome reprogramming compared to untreated controls, which reverted upon drug washout to that of the treatment naïve state. While cell cycle-rel...