Exploiting Temporal Collateral Sensitivity in Tumor Clonal Evolution. Zhao, B., Sedlak, J., C., Srinivas, R., Creixell, P., Pritchard, J., R., Tidor, B., Lauffenburger, D., A., & Hemann, M., T. Cell, 165(1):234-246, Elsevier Inc., 3, 2016. ![Exploiting Temporal Collateral Sensitivity in Tumor Clonal Evolution [link]](https://bibbase.org/img/filetypes/link.svg "link")
Website doi abstract bibtex Summary The prevailing approach to addressing secondary drug resistance in cancer focuses on treating the resistance mechanisms at relapse. However, the dynamic nature of clonal evolution, along with potential fitness costs and cost compensations, may present exploitable vulnerabilities - A notion that we term "temporal collateral sensitivity." Using a combined pharmacological screen and drug resistance selection approach in a murine model of Ph+ acute lymphoblastic leukemia, we indeed find that temporal and/or persistent collateral sensitivity to non-classical BCR-ABL1 drugs arises in emergent tumor subpopulations during the evolution of resistance toward initial treatment with BCR-ABL1-targeted inhibitors. We determined the sensitization mechanism via genotypic, phenotypic, signaling, and binding measurements in combination with computational models and demonstrated significant overall survival extension in mice. Additional stochastic mathematical models and small-molecule screens extended our insights, indicating the value of focusing on evolutionary trajectories and pharmacological profiles to identify new strategies to treat dynamic tumor vulnerabilities.
@article{
title = {Exploiting Temporal Collateral Sensitivity in Tumor Clonal Evolution},
type = {article},
year = {2016},
pages = {234-246},
volume = {165},
websites = {http://linkinghub.elsevier.com/retrieve/pii/S0092867416300599,http://dx.doi.org/10.1016/j.cell.2016.01.045,https://linkinghub.elsevier.com/retrieve/pii/S0092867416300599},
month = {3},
publisher = {Elsevier Inc.},
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abstract = {Summary The prevailing approach to addressing secondary drug resistance in cancer focuses on treating the resistance mechanisms at relapse. However, the dynamic nature of clonal evolution, along with potential fitness costs and cost compensations, may present exploitable vulnerabilities - A notion that we term "temporal collateral sensitivity." Using a combined pharmacological screen and drug resistance selection approach in a murine model of Ph+ acute lymphoblastic leukemia, we indeed find that temporal and/or persistent collateral sensitivity to non-classical BCR-ABL1 drugs arises in emergent tumor subpopulations during the evolution of resistance toward initial treatment with BCR-ABL1-targeted inhibitors. We determined the sensitization mechanism via genotypic, phenotypic, signaling, and binding measurements in combination with computational models and demonstrated significant overall survival extension in mice. Additional stochastic mathematical models and small-molecule screens extended our insights, indicating the value of focusing on evolutionary trajectories and pharmacological profiles to identify new strategies to treat dynamic tumor vulnerabilities.},
bibtype = {article},
author = {Zhao, Boyang and Sedlak, Joseph C. and Srinivas, Raja and Creixell, Pau and Pritchard, Justin R. and Tidor, Bruce and Lauffenburger, Douglas A. and Hemann, Michael T.},
doi = {10.1016/j.cell.2016.01.045},
journal = {Cell},
number = {1},
keywords = {BCR-ABL1 inhibitor,cancer type: ALL,clonal evolution,collateral sensitivity,drug combination,drug resistance,mathematical modeling,tumor heterogeneity}
}
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