Significance
Uncontrolled cell division is a hallmark of cancer. Drugs that inhibit the cell cycle in tumor cells, such as palbociclib, have improved health outcomes in Estrogen receptor–positive, human epidermal growth factor 2 receptor–negative (ER+/HER2−) breast cancer patients. However, it is common for a small percentage of tumor cells to keep dividing in the presence of the drug, revealing a gap in our understanding of mechanisms that underlie resistance. Here, we show that flexibility, or plasticity, in the cell cycle allows some tumor cells to escape treatment by taking different cell cycle “paths.” Our work could lead to improved treatment strategies in ER+/HER2− breast cancer and points to cell cycle plasticity as a potential driver of therapeutic resistance in human tumors.
Abstract
The CDK4/6 inhibitor palbociclib blocks cell cycle progression in Estrogen receptor–positive, human epidermal growth factor 2 receptor–negative (ER+/HER2−) breast tumor cells. Despite the drug’s success in improving patient outcomes, a small percentage of tumor cells continues to divide in the presence of palbociclib—a phenomenon we refer to as fractional resistance. It is critical to understand the cellular mechanisms underlying fractional resistance because the precise percentage of resistant cells in patient tissue is a strong predictor of clinical outcomes. Here, we hypothesize that fractional resistance arises from cell-to-cell differences in core cell cycle regulators that allow a subset of cells to escape CDK4/6 inhibitor therapy. We used multiplex, single-cell imaging to identify fractionally resistant cells in both cultured and primary breast tumor samples resected from patients. Resistant cells showed premature accumulation of multiple G1 regulators including E2F1, retinoblastoma protein, and CDK2, as well as enhanced sensitivity to pharmacological inhibition of CDK2 activity. Using trajectory inference approaches, we show how plasticity among cell cycle regulators gives rise to alternate cell cycle “paths” that allow individual tumor cells to escape palbociclib treatment. Understanding drivers of cell cycle plasticity, and how to eliminate resistant cell cycle paths, could lead to improved cancer therapies targeting fractionally resistant cells to improve patient outcomes.
