title: Analysis of compound synergy in high-throughput cellular screens by population-based lifetime modeling.
abstract: Despite the successful introduction of potent anti-cancer therapeutics, most of these drugs lead to only modest tumor-shrinkage or transient responses, followed by re-growth of tumors. Combining different compounds has resulted in enhanced tumor control and prolonged survival. However, methods querying the efficacy of such combinations have been hampered by limited scalability, analytical resolution, statistical feasibility, or a combination thereof. We have developed a theoretical framework modeling cellular viability as a stochastic lifetime process to determine synergistic compound combinations from high-throughput cellular screens. We apply our method to data derived from chemical perturbations of 65 cancer cell lines with two inhibitors. Our analysis revealed synergy for the combination of both compounds in subsets of cell lines. By contrast, in cell lines in which inhibition of one of both targets was sufficient to induce cell death, no synergy was detected, compatible with the topology of the oncogenically activated signaling network. In summary, we provide a tool for the measurement of synergy strength for combination perturbation experiments that might help define pathway topologies and direct clinical trials.
authors.affiliation: Max Planck Institute for Neurological Research with Klaus-Joachim-Zülch Laboratories of the Max Planck Society and the Medical Faculty of the University of Köln, Max Planck Society, Köln, Germany. peifer@nf.mpg.de
authors.forename: Martin
authors.initials: M
authors.lastname: Peifer
authors.forename: Jonathan
authors.initials: J
authors.lastname: Weiss
authors.forename: Martin L
authors.initials: ML
authors.lastname: Sos
authors.forename: Mirjam
authors.initials: M
authors.lastname: Koker
authors.forename: Stefanie
authors.initials: S
authors.lastname: Heynck
authors.forename: Christian
authors.initials: C
authors.lastname: Netzer
authors.forename: Stefanie
authors.initials: S
authors.lastname: Fischer
authors.forename: Haridas
authors.initials: H
authors.lastname: Rode
authors.forename: Daniel
authors.initials: D
authors.lastname: Rauh
authors.forename: Jörg
authors.initials: J
authors.lastname: Rahnenführer
authors.forename: Roman K
authors.initials: RK
authors.lastname: Thomas
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D006801:Humans; D008962:Models, Theoretical; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D013269:Stochastic Processes
chemical_list: D000970:Antineoplastic Agents