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bioRxiv · 10.1101/2024.07.05.602281

Transcriptional Characterization of Resistance in Early Drug Response

Ruoff, C.·Mitchell, A.·Mondal, P.·Gopalan, V.·Gottesman, M.·Hannenhalli, S.
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Abstract

Therapeutic resistance is a major cause of cancer treatment failure, with increasing evidence suggesting a non-genetic basis. This non-genetic resistance is often due to drug-resistant transcriptional cell states, either induced by treatment or pre-existing in some cells. However, the connection between early cellular drug response and long-term resistance is poorly understood. Moreover, it is unknown whether resistance-associated early transcriptional responses are evolutionarily conserved. Integrating long-term drug resistance and early drug response data across multiple cancer cell lines, bacteria, and yeast, our findings indicate that cancer states in drug-naive populations and shortly after treatment share transcriptional properties with fully resistant populations, some of which are evolutionarily conserved. CRISPR-Cas9 knockout of resistant states markers increased sensitivity to Prexasertib in ovarian cancer cells. Finally, early resistant state signatures discriminated therapy responders from non-responders across multiple human cancer trials, and distinguished premalignant breast lesions that progress to malignancy from those that do not.

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Ruoff, C., Mitchell, A., Mondal, P., Gopalan, V., Gottesman, M., Hannenhalli, S.. 2024-07-10. Transcriptional Characterization of Resistance in Early Drug Response. https://doi.org/10.1101/2024.07.05.602281

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