Proliferation (GR)

Documentation Index

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Why Use This Engine?

In the documentation below, we will use Revilico’s Proliferation (GR) assay engine to compute growth rate-corrected drug sensitivity metrics that distinguish whether a compound is slowing cell division (cytostatic) or actively killing cells (cytotoxic). Standard IC50 measurements confound these two fundamentally different drug effects. The GR correction method (Hafner et al., 2016) removes the dependence of apparent drug potency on the cell line’s intrinsic proliferation rate, providing more consistent and mechanistically interpretable metrics across cell lines with different doubling times.

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Background

A drug that arrests cells in G1 without killing them will appear potent in a standard endpoint viability assay simply because cells in a rapidly dividing control well have doubled or tripled in number while treated cells have not. The measured IC50 is therefore a function of both the drug’s mechanism and the cell line’s proliferation rate, making cross-cell-line comparisons unreliable. The GR correction method accounts for this by normalizing the measured cell count response to the expected cell count in the absence of drug, based on the known cell doubling time. The GR value maps the response to a scale where +1 indicates no drug effect (full growth), 0 indicates cytostasis (alive but not dividing), and -1 indicates a net cytotoxic effect (more cells dying than dividing). This scale is mechanistically interpretable: drugs with GR_max near 0 are pure cytostatic agents (kinase inhibitors at therapeutic doses), while drugs with GR_max near -1 are cytotoxic agents (chemotherapies).

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Simulation Model

The GR value at concentration $c$ is computed directly from the GNN+MLP viability prediction $v(c)$: $$\text{GR}(c) = 2 \cdot v(c) - 1 + \varepsilon, \quad \varepsilon \sim \mathcal{N}(0, 0.08^2), \quad \text{clamped to } [-1, +1]$$ This linear mapping reflects the mathematical relationship between normalized viability and GR: a viability of 1.0 (no effect) maps to GR = +1, viability of 0.5 maps to GR = 0 (cytostasis), and viability of 0 maps to GR = -1 (complete cytotoxicity). GR50 is the concentration at which GR = 0.5 (half-maximal growth inhibition), extracted from the GR dose-response curve and analogous to IC50 but corrected for proliferation rate. Doubling time is modeled as increasing with drug stress: $$\tau(c) = \frac{\tau_0}{\max(v(c), 0.05)} \cdot \eta_\tau, \quad \eta_\tau \sim \mathcal{LN}(0, 0.10^2)$$ Basal doubling times by cell line: EdU incorporation (fraction of cells in S-phase, measured by 5-ethynyl-2’-deoxyuridine incorporation as a proxy for active DNA synthesis): $$\text{EdU\%}(c) = v(c) \times 55 + \varepsilon_{\text{EdU}}, \quad \varepsilon_{\text{EdU}} \sim \mathcal{N}(0, 6^2)$$ The scaling factor of 55% reflects the average S-phase fraction of cycling cancer cells in an asynchronous population.

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GR Metric Interpretation

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Parameters

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Outputs

• GR value: Growth rate-corrected drug effect at each concentration per cell line (range -1 to +1)
• GR50: Concentration at half-maximal growth inhibition per cell line
• GR_max: GR value at saturating drug concentration (cytotoxicity ceiling)
• Doubling time: Drug-extended cell cycle duration per cell line per concentration
• EdU %: Fraction of cells in S-phase as a DNA synthesis proxy
• GR dose-response curves: Per-cell-line GR vs. log concentration curves
• Comparative GR plot: All cell lines overlaid with GR = 0 cytostasis reference line
• 96-well heatmap: Plate-view colored by GR value
• GR50 waterfall: Cell lines ranked by GR50, analogous to the IC50 waterfall in RevViability