Cell-to-Cell Variation in p53 Dynamics Leads to Fractional Killing

• In response to a drug, single cells show different fates and rates of p53 induction
• The p53 threshold required to enact apoptosis rises with time
• Drug efficacy is enhanced by accelerating the rate of p53 induction
• Inhibition of anti-apoptotic proteins reduces the increase in threshold over time

SummaryMany chemotherapeutic drugs kill only a fraction of cancer cells, limiting their efficacy. We used live-cell imaging to investigate the role of p53 dynamics in fractional killing of colon cancer cells in response to chemotherapy. We found that both surviving and dying cells reach similar levels of p53, indicating that cell death is not determined by a fixed p53 threshold. Instead, a cell’s probability of death depends on the time and levels of p53. Cells must reach a threshold level of p53 to execute apoptosis, and this threshold increases with time. The increase in p53 apoptotic threshold is due to drug-dependent induction of anti-apoptotic genes, predominantly in the inhibitors of apoptosis (IAP) family. Our study underlines the importance of measuring the dynamics of key players in response to chemotherapy to determine mechanisms of resistance and optimize the timing of combination therapy.

Graphical AbstractFigure optionsDownload high-quality image (255 K)Download as PowerPoint slide