Fig. 6: Pharmacological profiling reveal axis-specific drug vulnerabilities and resistance.

a Volcano plots showing pharmacotranscriptomic comparisons of drug sensitivities across cells lines ranking high and low along with the MYC-, KRAS- and hypoxia axis. b Schematic overview of pharmacological profiling of hypoxic and normoxic cell populations to highlight potential differences in drug sensitivities along this axis (left). c Western blots analysis highlights increased CA9 expression with decreasing oxygen levels indicating a downstream response to hypoxia. Relative expression of palisading cells around necrosis (PAN) associated marker AKAP12 by western blot reveals increased expression in hypoxic conditions. Vinculin serves as a loading control. Densitometry analysis of AKAP12 western blots highlights an average 2-fold increase between 21% oxygen and 0.2% oxygen conditions across 4 different cell lines. d Differential viability of hypoxic versus normoxic cell populations (y-axis) upon treatment with 188 compounds and averaged over two replicates, overall cell viability is the average of the cell populations against the reference population (x-axis) and targets with the greatest differential viability are colored by the target as specified in the top legends. Blue dots represent compounds with the minimal differential response. d Relative viability effects on GSC proliferation in a kinome screen under differential oxygen concentrations. e Spheroid images upon treatment of GSK1398477, a PDGFRB inhibitor, in hypoxic and normoxic conditions. f Model of the heterogeneous co-existence of GBM populations driven by the KRAS or MYC target genes and signatures defined on the hypoxia pathway axis. Source data are provided as a Source Data file.