FIGURE 1 from A Novel Class of Ribosome Modulating Agents Exploits Cancer Ribosome Heterogeneity to Selectively Target the CMS2 Subtype of Colorectal Cancer
posted on 2023-06-05, 14:20authored byEsteban Terzo, Shruti A. Apte, Simran Padhye, Saleh Rashed, Wesley Austin, Michael Caponegro, Anupama Reddy, Shuhao Shi, Christy Wang, Roger B. Clark, David Sidransky, Vijay Modur, Vasudeo Badarinarayana
<p>ZKN-157 selectively inhibits growth and protein translation in a sensitive colorectal cancer cell line. <b>A,</b> Chemical structure of ZKN-157. <b>B,</b> Percent response curves showing the effect of ZKN-157 treatment in COLO320DM and SW1417 cells. Curves are representative of three independent biological experiments. Error bars are SDs of two technical replicates. Table shows GI<sub>50</sub> and LD50 values <b>C,</b> Cartoon showing the metabolic labeling assay workflow. <b>D,</b> Representative Western blot membranes of two independent biological experiments showing: -AHA (no AHA reagent added to lysate), CHX (positive control for translation inhibition), DMSO (negative control), and ZKN-157 treatment (40 μmol/L). Equal protein amount for all samples were used for click chemistry reaction. Samples resuspended in equal volume were loaded on gel. Intensity from densitometry of ZKN-157–treated samples was normalized to those of DMSO samples to calculate relative protein translation. Bar graph shows normalized values from two independent experiments. Error bars are SDs.</p>
This study demonstrates that ribosome heterogeneity in cancer can be exploited to develop selective ribogenesis inhibitors. The colorectal cancer CMS2 subtype, with a high unmet need for therapeutics, shows vulnerability to our novel selective ribosome modulator. The mechanism suggests that other cancer subtypes with high MYC activation could also be targeted.