Fig. 6. PDxO drug screening shows concordance with in vivo data and identifies birinapant as a potential therapy for some TNBC tumors.
a, Unsupervised clustering of 16 PDxO models and 45 screened compounds. Color indicates GRaoc statistics (darker colors indicate cytotoxicity, and lighter colors indicate growth). Annotations indicate HR status. b, An illustration of dose–response curve statistics that can be calculated using the R package GRmetrics. The y axis displays growth rate-adjusted estimates from the CellTiter-Glo 3D (CTG-3D) cell viability assays. The x axis shows log fold change of eight-point dose concentrations. Each dot represents 1 of 12 replicates (3 biological replicates and 4 technical replicates each). Annotations include half-maximal effective concentration (EC50), GR50 (concentration at which the GR value is 0.5), cytostatic (concentration at which the model is neither growing nor shrinking) and GRaoc (the area over the dose–response curve that estimates both sensitivity and cytotoxicity). c, Ordered models based on GRaoc for navitoclax sensitivity. High values with darker colors suggest a cytotoxic response to the compound. Drug concentrations are micromolar units. The colors of the model identifiers correspond to in vivo data in d. The heat map displays drug response to navitoclax in PDxO screens. The coloration indicates CTG-3D cell viability assays in PDxO screens that were normalized to day 0 ranging from 0 (black, cytotoxic) to 3 (yellow, growth). Models are sorted by GRaoc estimate. d, Responses to navitoclax in vivo for the most sensitive model predicted by PDxO screening (HCI-010) and four others: HCI-024, HCI-015, HCI-002 and HCI-027. Data are shown as mean ± s.e.m. Treatment groups for all PDX lines are composed of n = 3 mice; vehicle groups for all PDX lines include n = 6 mice. e, Stacked heat map displays ordered GRaoc calculations for each model’s response to docetaxel from dark (cytotoxic) to light (growth). The colors of model identifiers correspond to in vivo modeling in f. The heat map displays drug response to docetaxel in PDxO screens. Drug concentrations are micromolar units. The coloration indicates CTG-3D cell viability assays in PDxO screens that were normalized to day 0 ranging from 0 (black, cytotoxic) to 2.5 (yellow, growth). Models are sorted by GRaoc estimate. f, Results of in vivo docetaxel treatment for HCI-023, HCI-015, HCI-019, HCI-016, HCI-002, HCI-027, HCI-010, HCI-024 and HCI-001. Data are shown as mean ± s.e.m. Treatment groups for all PDX lines include n = 3 mice; vehicle groups for all PDX lines include n = 6 mice.