Exploiting Temporal Collateral Sensitivity in Tumor Clonal Evolution

Boyang Zhao, Joseph C. Sedlak, Raja Srinivas, Pau Creixell, Justin R. Pritchard, Bruce Tidor, Douglas A. Lauffenburger, Michael T. Hemann

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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.

Original languageEnglish (US)
Pages (from-to)234-246
Number of pages13
JournalCell
Volume165
Issue number1
DOIs
StatePublished - Mar 24 2016

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All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Zhao, B., Sedlak, J. C., Srinivas, R., Creixell, P., Pritchard, J. R., Tidor, B., Lauffenburger, D. A., & Hemann, M. T. (2016). Exploiting Temporal Collateral Sensitivity in Tumor Clonal Evolution. Cell, 165(1), 234-246. https://doi.org/10.1016/j.cell.2016.01.045