Ploidy shapes gemcitabine response through altered potency and delayed cell death
- 1H. Lee Moffitt Cancer Center
Abstract
Aberrant tumor ploidy is a near-universal hallmark of cancer and increasingly recognized as a determinant of therapeutic response, but the mechanisms by which ploidy shapes sensitivity to specific cytotoxic agents remain unclear. Here, we investigated the relationship between ploidy and therapeutic response using pharmacogenomic reanalysis, isogenic cancer cell systems, live-cell imaging, intracellular pharmacokinetic/ pharmacodynamic (PK/PD) measurements, and mathematical modeling. Across public pharmacogenomic datasets, gemcitabine emerged as a low-ploidy-selective cytotoxic agent. In matched isogenic low- and high-ploidy cell systems, higher-ploidy cells were consistently less sensitive to gemcitabine across multiple lineages. Live-cell imaging and PK/PD measurements in near-diploid and near-tetraploid SUM-159 cells showed that both states formed intracellular dFdCTP, active form of gemcitabine; but, high-ploidy cells exhibited weaker and slower treatment responses, with delayed accumulation of cell death. To quantify these differences, we developed a delay-aware live/dead model driven by intracellular dFdCTP exposure. The model identified both reduced effective gemcitabine potency and a substantially longer delay from intracellular drug action to observed death in high-ploidy cells (17.5 hours in near-diploid cells versus 42.5 hours in near-tetraploid cells). Interpreting these fitted quantities alongside checkpoint signaling and metabolomic profiling suggests that high-ploidy cells convert intracellular gemcitabine exposure less efficiently into replication-stress signaling, nucleotide-metabolic disruption, and cytotoxic commitment. Together, these results establish ploidy as a determinant of both the magnitude and timing of gemcitabine response and provide a quantitative framework for linking intracellular drug exposure to delayed cytotoxic outcomes across ploidy states.
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BibTeX
@misc{tagal2026ploidy,
title = {{Ploidy shapes gemcitabine response through altered potency and delayed cell death}},
author = {V. Tagal and J. P. Cole and T. Li and R. J. Kumar and J. Albrecht and P. Shrestha and D. Ilter and D. Miroshnychenko and S. Drapela and K. D. Olumoyin and J. Kyei and M. Davies and A. D. Marusyk and S. Maudsley and X. Yu and A. P. Gomes and I. El-Naqa and D. R. Duckett and H. S. Han and N. Andor},
howpublished = {bioRxiv},
year = {2026},
month = jun,
doi = {10.64898/2026.06.01.729318},
url = {https://www.biorxiv.org/content/10.64898/2026.06.01.729318v2},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Ploidy shapes gemcitabine response through altered potency and delayed cell death
AU - V. Tagal
AU - J. P. Cole
AU - T. Li
AU - R. J. Kumar
AU - J. Albrecht
AU - P. Shrestha
AU - D. Ilter
AU - D. Miroshnychenko
AU - S. Drapela
AU - K. D. Olumoyin
AU - J. Kyei
AU - M. Davies
AU - A. D. Marusyk
AU - S. Maudsley
AU - X. Yu
AU - A. P. Gomes
AU - I. El-Naqa
AU - D. R. Duckett
AU - H. S. Han
AU - N. Andor
PY - 2026
DA - 2026/06/01
PB - bioRxiv
DO - 10.64898/2026.06.01.729318
UR - https://www.biorxiv.org/content/10.64898/2026.06.01.729318v2
AB - Aberrant tumor ploidy is a near-universal hallmark of cancer and increasingly recognized as a determinant of therapeutic response, but the mechanisms by which ploidy shapes sensitivity to specific cytotoxic agents remain unclear. Here, we investigated the relationship between ploidy and therapeutic response using pharmacogenomic reanalysis, isogenic cancer cell systems, live-cell imaging, intracellular pharmacokinetic/ pharmacodynamic (PK/PD) measurements, and mathematical modeling. Across public pharmacogenomic datasets, gemcitabine emerged as a low-ploidy-selective cytotoxic agent. In matched isogenic low- and high-ploidy cell systems, higher-ploidy cells were consistently less sensitive to gemcitabine across multiple lineages. Live-cell imaging and PK/PD measurements in near-diploid and near-tetraploid SUM-159 cells showed that both states formed intracellular dFdCTP, active form of gemcitabine; but, high-ploidy cells exhibited weaker and slower treatment responses, with delayed accumulation of cell death. To quantify these differences, we developed a delay-aware live/dead model driven by intracellular dFdCTP exposure. The model identified both reduced effective gemcitabine potency and a substantially longer delay from intracellular drug action to observed death in high-ploidy cells (17.5 hours in near-diploid cells versus 42.5 hours in near-tetraploid cells). Interpreting these fitted quantities alongside checkpoint signaling and metabolomic profiling suggests that high-ploidy cells convert intracellular gemcitabine exposure less efficiently into replication-stress signaling, nucleotide-metabolic disruption, and cytotoxic commitment. Together, these results establish ploidy as a determinant of both the magnitude and timing of gemcitabine response and provide a quantitative framework for linking intracellular drug exposure to delayed cytotoxic outcomes across ploidy states.
ER -