Common and cell-type specific responses to anti-cancer drugs revealed by high throughput transcript profiling

Abstract

More effective use of targeted anti-cancer drugs depends on elucidating the connection between the molecular states induced by drug treatment and the cellular phenotypes controlled by these states, such as cytostasis and death. This is particularly true when mutation of a single gene is inadequate as a predictor of drug response. The current paper describes a data set of ~600 drug cell line pairs collected as part of the NIH LINCS Program (http://www.lincsproject.org/) in which molecular data (reduced dimensionality transcript L1000 profiles) were recorded across dose and time in parallel with phenotypic data on cellular cytostasis and cytotoxicity. We report that transcriptional and phenotypic responses correlate with each other in general, but whereas inhibitors of chaperones and cell cycle kinases induce similar transcriptional changes across cell lines, changes induced by drugs that inhibit intra-cellular signaling kinases are cell-type specific. In some drug/cell line pairs significant changes in transcription are observed without a change in cell growth or survival; analysis of such pairs identifies drug equivalence classes and, in one case, synergistic drug interactions. In this case, synergy involves cell-type specific suppression of an adaptive drug response.