Exploiting Temporal Collateral Sensitivity in Tumor Clonal Evolution

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

Research output: Contribution to journalArticle

40 Citations (Scopus)

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

Fingerprint

Clonal Evolution
Tumors
Drug Resistance
Pharmaceutical Preparations
Pharmacology
Costs and Cost Analysis
Neoplasms
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Compensation and Redress
Costs
Theoretical Models
Trajectories
Mathematical models
Recurrence
Molecules

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., Tidor, B., ... 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
Zhao, Boyang ; Sedlak, Joseph C. ; Srinivas, Raja ; Creixell, Pau ; Pritchard, Justin ; Tidor, Bruce ; Lauffenburger, Douglas A. ; Hemann, Michael T. / Exploiting Temporal Collateral Sensitivity in Tumor Clonal Evolution. In: Cell. 2016 ; Vol. 165, No. 1. pp. 234-246.
@article{8775621e99a24e0e96b5cda38633d1cf,
title = "Exploiting Temporal Collateral Sensitivity in Tumor Clonal Evolution",
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.",
author = "Boyang Zhao and Sedlak, {Joseph C.} and Raja Srinivas and Pau Creixell and Justin Pritchard and Bruce Tidor and Lauffenburger, {Douglas A.} and Hemann, {Michael T.}",
year = "2016",
month = "3",
day = "24",
doi = "10.1016/j.cell.2016.01.045",
language = "English (US)",
volume = "165",
pages = "234--246",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "1",

}

Zhao, B, Sedlak, JC, Srinivas, R, Creixell, P, Pritchard, J, Tidor, B, Lauffenburger, DA & Hemann, MT 2016, 'Exploiting Temporal Collateral Sensitivity in Tumor Clonal Evolution', Cell, vol. 165, no. 1, pp. 234-246. https://doi.org/10.1016/j.cell.2016.01.045

Exploiting Temporal Collateral Sensitivity in Tumor Clonal Evolution. / Zhao, Boyang; Sedlak, Joseph C.; Srinivas, Raja; Creixell, Pau; Pritchard, Justin; Tidor, Bruce; Lauffenburger, Douglas A.; Hemann, Michael T.

In: Cell, Vol. 165, No. 1, 24.03.2016, p. 234-246.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Exploiting Temporal Collateral Sensitivity in Tumor Clonal Evolution

AU - Zhao, Boyang

AU - Sedlak, Joseph C.

AU - Srinivas, Raja

AU - Creixell, Pau

AU - Pritchard, Justin

AU - Tidor, Bruce

AU - Lauffenburger, Douglas A.

AU - Hemann, Michael T.

PY - 2016/3/24

Y1 - 2016/3/24

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84975717783&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84975717783&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2016.01.045

DO - 10.1016/j.cell.2016.01.045

M3 - Article

C2 - 26924578

AN - SCOPUS:84975717783

VL - 165

SP - 234

EP - 246

JO - Cell

JF - Cell

SN - 0092-8674

IS - 1

ER -

Zhao B, Sedlak JC, Srinivas R, Creixell P, Pritchard J, Tidor B et al. Exploiting Temporal Collateral Sensitivity in Tumor Clonal Evolution. Cell. 2016 Mar 24;165(1):234-246. https://doi.org/10.1016/j.cell.2016.01.045