Transcriptional Characterization of Resistance in Early Drug Response

Therapeutic resistance is the leading cause of treatment failure and death from cancer. While resistance can be driven by genetic mutations, mounting evidence also points to an epigenetic basis of resistance. Much of this epigenetic, or non-genetic, resistance has been attributed to drug-resistant transcriptional cell states that are either induced by drug treatment or pre-exist in a fraction of cells selected by treatment. However, the extent to which long-term resistance is manifested in the early inherent cellular response to drugs is poorly understood, and which aspects, if any, of this early response to drug-induced transcriptional response are evolutionarily conserved properties of cells. To address these questions, we integrate datasets of long-term drug resistance and early drug response data across multiple cell lines with drug response and resistance data from bacteria and yeast. Our findings suggest that cancer cell states in both the drug naive populations as well as in populations shortly after treatment share transcriptional properties with fully established resistant cell populations, and CRISPR-cas9 knockout of transcription factors predicted to regulate the resistant transcriptional programs result in increased drug sensitivity. Furthermore, the resistance states manifested as early drug response are evolutionarily conserved. Finally, we show that early resistant states discriminate responders from non-responders across multiple human cancer trials.