Expression levels of therapeutic targets as indicators of sensitivity to targeted therapeutics

Cancer precision medicine aims to predict the drug likely to yield the best response for a patient. Genomic sequencing of tumours is currently being used to better inform treatment options, however, this approach has had a limited clinical impact due to the paucity of actionable mutations. An alternative to mutation status is the use of gene expression signatures to predict response. Using data from two large-scale studies, The Genomics of Drug Sensitivity of Cancer (GDSC) and The Cancer Therapeutics Response Portal (CTRP), we investigated the relationship between the sensitivity of hundreds of cell lines to hundreds of drugs, and the relative expression levels of the targets these drugs are directed against. For approximately one third of the drugs considered (73/222 in GDSC and 131/360 in CTRP) sensitivity was significantly correlated with the expression of at least one of the known targets. Surprisingly for 8% of the annotated targets there was a significant anti-correlation between target expression and sensitivity. For several cases, this corresponded to drugs targeting multiple genes in the same family, with the expression of one target significantly correlated with sensitivity and another significantly anti-correlated suggesting a possible role in resistance. Furthermore, we identified non-target genes that are significantly correlated or anti-correlated with drug sensitivity, and find literature linking several to sensitization and resistance. Our analyses provide novel and important insights into both potential mechanisms of resistance and relative efficacy of drugs against the same target.