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Ploidy shapes gemcitabine response through altered potency and delayed cell death
Vural Tagal1, Tao Li1, Rikhil Kumar1
1H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
Biorxiv : the Preprint Server for Biology
|June 12, 2026
Summary
Tumor ploidy influences gemcitabine (a chemotherapy drug) effectiveness. High-ploidy cancer cells show reduced sensitivity and delayed cell death, impacting treatment outcomes.
Area of Science:
- Cancer Biology
- Pharmacology
- Mathematical Modeling
Background:
- Tumor ploidy is a key factor in cancer treatment response.
- Mechanisms linking ploidy to cytotoxic drug sensitivity are not well understood.
Purpose of the Study:
- Investigate the impact of tumor ploidy on gemcitabine response.
- Elucidate the quantitative relationship between ploidy, intracellular drug dynamics, and cell death.
Main Methods:
- Pharmacogenomic data reanalysis.
- Isogenic cell line studies (low- vs. high-ploidy).
- Live-cell imaging and intracellular pharmacokinetic/pharmacodynamic (PKPD) measurements.
- Development of a delay-aware mathematical model.
Main Results:
- Gemcitabine demonstrated selectivity for low-ploidy tumors across datasets.
- High-ploidy cells exhibited decreased gemcitabine sensitivity and delayed cell death.
- Mathematical modeling revealed reduced drug potency and significantly longer delays (17.5h vs. 42.5h) in high-ploidy cells.
- A nonlinear, ploidy-dependent dose-response relationship was identified.
Conclusions:
- Tumor ploidy significantly affects both the magnitude and timing of gemcitabine's cytotoxic effects.
- Ploidy is a critical determinant of cellular response to gemcitabine.
- A quantitative framework was established to connect intracellular drug exposure to delayed cell death across different ploidy states.
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