title: Exploiting Temporal Collateral Sensitivity in Tumor Clonal Evolution.
abstract: 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.
authors.affiliation: Computational and Systems Biology Program, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Boyang
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Harvard/MIT MD-PhD Program, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Sedlak
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Raja
authors.initials: R
authors.lastname: Srinivas
authors.affiliation: The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Pau
authors.initials: P
authors.lastname: Creixell
authors.affiliation: The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Justin R
authors.initials: JR
authors.lastname: Pritchard
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Tidor
authors.affiliation: The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: lauffen@mit.edu.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Lauffenburger
authors.affiliation: The David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Electronic address: hemann@mit.edu.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Hemann
mesh_terms: D000818:Animals; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D051379:Mice; D008954:Models, Biological; D010677:Philadelphia Chromosome; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000473:pathology; D051562:Proto-Oncogene Proteins c-bcr / Q000032:analysis / Q000235:genetics
chemical_list: D051562:Proto-Oncogene Proteins c-bcr