A patient-derived xenograft pre-clinical trial reveals treatment responses and a resistance mechanism to karonudib in metastatic melanoma

a Schematic overview of the experimental setup. Tumor biopsy from melanoma patient was serially transplanted twice in mice before being transplanted in mice treated with either karonudib or vehicle. For each patient, there was one mouse per treatment group, which was treated for 18 days before tumors were harvested and processed. Each tumor was snap-frozen for RNA analysis and embedded in paraffin for immunohistochemical straining. b Waterfall plot revealing the heterogenous response to karonudib. The samples are divided in three response groups, progression (blue), suppression (yellow), and regression (red). For treatment response catagorization, see Materials and methods. Comparison of average (±SEM) growth speed of karonudib treated vs. vehicle treated PDXes for (c) progression group, d suppression group, and e regression group. Individual growth curves are shown in supplemental figures S2-S4. f Kaplan–Meier graph showing the comparison of probability of progression-free survival in karonudib-treated mice (based on tumor doubling time) for the three response groups (see Materials and methods for criterion), Mantel–Cox test used for statistical analysis. g Quantification of immunohistochemical staining for the proliferation marker Ki-67 in vehicle vs. karonudib-treated PDXes, Student’s t test showing statistically significant difference between the two groups (p？=？0.0476). h Images of the xenograft sections stained with Ki-67 and used for the quantification in (g