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 R.
AU - Tidor, Bruce
AU - Lauffenburger, Douglas A.
AU - Hemann, Michael T.
N1 - Funding Information:
We thank Peter Bruno and Christian Braun for critical review and feedback on this manuscript, and Stuart Levine and Jie Wu from the MIT BioMicroCenter and Glen Paradis from the Koch Institute Flow Cytometry Core for services and advice. This work was supported by the Koch Institute Support (core) grant P30-CA14051 from the National Cancer Institute, the Integrative Cancer Biology Program grant U54-CA112967 (to M.T.H., D.A.L., and B.T.), the National Institutes of General Medical Sciences GM082209 (to B.T.), the Ludwig Foundation (to M.T.H.) and the Go Mitch Go Foundation (to M.T.H.). B.Z. and R.S. are supported by the NIH/NIGMS Interdepartmental Biotechnology Training Program 5T32GM008334. B.Z. is also supported by the National Science Foundation Research Fellowship under grant 1122374. P.C. is supported by postdoctoral fellowships of the Ludwig Fund and Helen Hay Whitney Foundation. B.Z. is a consultant for ARIAD Pharmaceuticals, Inc. J.R.P. is an employee and shareholder of ARIAD Pharmaceuticals, Inc. D.A.L. is a consultant/ advisory board member of Merrimack Pharmaceuticals, Genentech, and Complete Genomics. Received: September 8, 2015 Revised: December 19, 2015 Accepted: January 26, 2016 Published: February 25, 2016.
Funding Information:
We thank Peter Bruno and Christian Braun for critical review and feedback on this manuscript, and Stuart Levine and Jie Wu from the MIT BioMicroCenter and Glen Paradis from the Koch Institute Flow Cytometry Core for services and advice. This work was supported by the Koch Institute Support (core) grant P30-CA14051 from the National Cancer Institute, the Integrative Cancer Biology Program grant U54-CA112967 (to M.T.H., D.A.L., and B.T.), the National Institutes of General Medical Sciences GM082209 (to B.T.), the Ludwig Foundation (to M.T.H.) and the Go Mitch Go Foundation (to M.T.H.). B.Z. and R.S. are supported by the NIH/NIGMS Interdepartmental Biotechnology Training Program 5T32GM008334 . B.Z. is also supported by the National Science Foundation Research Fellowship under grant 1122374 . P.C. is supported by postdoctoral fellowships of the Ludwig Fund and Helen Hay Whitney Foundation . B.Z. is a consultant for ARIAD Pharmaceuticals, Inc. J.R.P. is an employee and shareholder of ARIAD Pharmaceuticals, Inc. D.A.L. is a consultant/advisory board member of Merrimack Pharmaceuticals, Genentech, and Complete Genomics.
Publisher Copyright:
© 2016 Elsevier Inc.
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.
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U2 - 10.1016/j.cell.2016.01.045
DO - 10.1016/j.cell.2016.01.045
M3 - Article
C2 - 26924578
AN - SCOPUS:84975717783
SN - 0092-8674
VL - 165
SP - 234
EP - 246
JO - Cell
JF - Cell
IS - 1
ER -
