Fig. 7: Conditional TP53 fitness in an MDM2-amplified PDX line.
From: Accurate determination of CRISPR-mediated gene fitness in transplantable tumours
a Upper panels show dose-response curves for nine PDX lines treated ex vivo with seven drugs in short-term organoid culture. Curves are shown as solid lines for PDXs that showed outlying fitness sensitivity to the drug-targeted gene(s) in the pooled in vivo CRISPR experiments. Lower panels show the median in vivo fitness of the indicated targeted gene against the half-maximal effective drug concentration (EC50). b Fitness measures for TP53 (guide TP53_3) and MDM2 (guide MDM2_1) (median, bars = 95% CI) in 17 PDX lines (60 PDX tumours total). PDX line C2553 is very sensitive to MDM2 targeting, while close to neutral fitness for TP53, consistent with MDM2 acting as a negative TP53 regulator. c Chromosome 12 copy number profile for PDX line C2553, inferred by TITAN from whole genome sequence data. Copy number amplicon including MDM2 gene is indicated. d Comparison of in vivo fitness and rank measurements for C2553 treated with MDM2 inhibitor Idasanutlin or vehicle control (median, bars = 95% CI. PDX tumours: drug-treated 2, vehicle 1.) TP53 shows a shift to positive fitness under drug treatment compared with control, consistent with a model in which pharmacological MDM2 inhibition causes reversion to a TP53 wild-type phenotype. Source data are provided as Source Data files.
