Registered report: A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations

Abstract

The Reproducibility Project: Cancer Biology seeks to address growing concerns about reproducibility in scientific research by conducting replications of selected experiments from a substantial number of high-profile papers in the field of cancer biology. The papers, which were published between 2010 and 2012, were selected on the basis of citations and Altmetric scores (Errington et al., 2014). This Registered Report describes the proposed replication plan of experiments from “A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations” by Sharma and colleagues, published in Cell in 2010 (Sharma et al., 2010). Sharma and colleagues demonstrated that prolonged exposure of cancer cells to TKIs give rise to small populations of “drug tolerant persisters” (DTPs) (Figure 1B-C) that were reversed during subsequent maintenance under drug-free conditions (Figures 1E, 2B and 2E). DTPs exhibited reduced histone acetylation and sensitivity to HDAC inhibitors (HDIs) (Figure 4A-B). Drug sensitivity was restored with co-treatment of either HDIs or an IGF-1R inhibitor, in combination with TKIs (Figure 5A-B). Inhibition of IGF-1R activation also led to decreased KDM5A expression and restoration of H3K4 methylation, suggesting a direct link between the IGF-1R signaling pathway and KDM5A function (Figure 7A, 7C, and 7I). The Reproducibility Project: Cancer Biology is a collaboration between the Center for Open Science and Science Exchange and the results of the replications will be published in eLife.