Identifying states of collateral sensitivity during the evolution of therapeutic resistance in Ewing’s sarcoma
Identifying states of collateral sensitivity during the evolution of therapeutic resistance in Ewing’s sarcoma
ABSTRACT Ewing’s sarcoma (EWS) is the second most common primary malignant bone cancer in children. Advances in the treatment of EWS are desperately needed, particularly in the case of metastatic disease. A deeper understanding of collateral sensitivity, where the evolution of therapeutic resistance to one drug aligns with sensitivity to another drug, may improve our ability to effectively target this disease. For the first time in a solid tumor, we examine the repeatability of collateral sensitivity in EWS cell lines over time as evolutionary replicates evolve resistance to standard treatment. In doing so, we produced a temporal collateral sensitivity map that allows us to examine the evolution of collateral sensitivity and resistance in EWS. We found that the evolution of collateral sensitivity and resistance was predictable with some drugs, but had significant variation in response to other drugs. Samples that were most sensitive and most resistant to all drugs were compared using differential gene expression. Using this map of temporal collateral sensitivity in EWS, we can see that the path towards collateral sensitivity is not always repeatable, nor is there always a clear trajectory towards resistance or sensitivity. Identifying transcriptomic changes that accompany these states of transient collateral sensitivity could improve treatment planning for EWS patients.
Dhawan Andrew、Anderson Peter、Scarborough Jessica A.、McClure Erin、Durmaz Arda、Lessnick Stephen L.、Scott Jacob G.、Hitomi Masahiro
Neurological Institute, Cleveland ClinicHeme/Onc/BMT, Cleveland ClinicTranslational Hematology and Oncology Research, Taussig Cancer Institute||Systems Biology and Bioinformatics Department, School of Medicine, Case Western Reserve UniversityTranslational Hematology and Oncology Research, Taussig Cancer Institute||Morsani College of Medicine, University of South FloridaTranslational Hematology and Oncology Research, Taussig Cancer Institute||Systems Biology and Bioinformatics Department, School of Medicine, Case Western Reserve UniversityCenter for Childhood Cancer and Blood Diseases, Abigail Wexner Research Institute at Nationwide Children?ˉs Hospital||Division of Pediatric Heme/Onc/BMT, The Ohio State UniversityTranslational Hematology and Oncology Research, Taussig Cancer Institute||Systems Biology and Bioinformatics Department, School of Medicine, Case Western Reserve University||Department of Radiation Oncology, Cleveland ClinicTranslational Hematology and Oncology Research, Taussig Cancer Institute
肿瘤学医学研究方法基础医学
Dhawan Andrew,Anderson Peter,Scarborough Jessica A.,McClure Erin,Durmaz Arda,Lessnick Stephen L.,Scott Jacob G.,Hitomi Masahiro.Identifying states of collateral sensitivity during the evolution of therapeutic resistance in Ewing’s sarcoma[EB/OL].(2025-03-28)[2025-07-16].https://www.biorxiv.org/content/10.1101/2020.02.11.943936.点此复制
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