Ruoff Cole, Mitchell Allision, Mondal Priya, Gopalan Vishaka, Singh Arashdeep, Gottesman Michael, Hannenhalli Sridhar
Cancer Data Science Lab, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA.
Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, 20892, USA.
bioRxiv. 2025 May 18:2024.07.05.602281. doi: 10.1101/2024.07.05.602281.
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.
治疗耐药性是癌症治疗失败的主要原因，越来越多的证据表明其存在非遗传基础。这种非遗传耐药性通常归因于耐药性转录细胞状态，该状态要么由治疗诱导产生，要么在某些细胞中预先存在。然而，早期细胞药物反应与长期耐药性之间的联系却鲜为人知。此外，与耐药性相关的早期转录反应在进化上是否保守也尚不清楚。通过整合多个癌细胞系、细菌和酵母的长期耐药性和早期药物反应数据，我们的研究结果表明，未经治疗的群体以及治疗后不久的癌症状态与完全耐药群体具有共同的转录特性，其中一些特性在进化上是保守的。对耐药状态标记物进行CRISPR-Cas9基因敲除可增加卵巢癌细胞对Prexasertib的敏感性。最后，早期耐药状态特征在多项人类癌症试验中区分了治疗反应者与无反应者，并区分了会发展为恶性肿瘤的癌前乳腺病变与不会发展为恶性肿瘤 的病变。
