Identifying States of Collateral Sensitivity during the Evolution of Therapeutic Resistance in Ewing's Sarcoma
Jessica A. Scarborough,
Erin McClure,
Peter Anderson,
Andrew Dhawan,
Arda Durmaz,
Stephen L. Lessnick,
Masahiro Hitomi,
Jacob G. Scott
Affiliations
Jessica A. Scarborough
Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44106, USA; Systems Biology and Bioinformatics Department, School of Medicine, Case Western Reserve University, Cleveland OH 44106, USA
Erin McClure
Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44106, USA; Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
Peter Anderson
Heme/Onc/BMT, Cleveland Clinic, Cleveland, OH 44106, USA
Andrew Dhawan
Neurological Institute, Cleveland Clinic, Cleveland, OH 44106, USA
Arda Durmaz
Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44106, USA; Systems Biology and Bioinformatics Department, School of Medicine, Case Western Reserve University, Cleveland OH 44106, USA
Stephen L. Lessnick
Center for Childhood Cancer and Blood Diseases, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA; Division of Pediatric Heme/Onc/BMT, The Ohio State University, Columbus, OH 43205, USA
Masahiro Hitomi
Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44106, USA
Jacob G. Scott
Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44106, USA; Systems Biology and Bioinformatics Department, School of Medicine, Case Western Reserve University, Cleveland OH 44106, USA; Department of Radiation Oncology, Cleveland Clinic, Cleveland, OH 44106, USA; Corresponding author
Summary: Advances in the treatment of Ewing's sarcoma (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 produced a temporal collateral sensitivity map that demonstrates the evolution of collateral sensitivity and resistance in EWS. We found that the evolution of collateral resistance was predictable with some drugs but had significant variation in response to other drugs. Using this map of temporal collateral sensitivity in EWS, we can see that the path toward collateral sensitivity is not always repeatable, nor is there always a clear trajectory toward resistance or sensitivity. Identifying transcriptomic changes that accompany these states of transient collateral sensitivity could improve treatment planning for patients with EWS.
