A Human Ribonuclease Variant and ERK-Pathway Inhibitors Exhibit Highly Synergistic Toxicity for Cancer Cells
Name
nihms-1508948.pdf
Description
Accepted version
Size
1.91 MB
Format
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Checksum (MD5)
21a576889feec3fa0051d874a363789c
Author(s)
Hoang, Trish T.
Tanrikulu, Ismet Caglar
Vatland, Quinn A.
Hoang, Trieu M.
Raines, Ronald T
Date Issued
December 2018
Journal
Molecular Cancer Therapeutics
Publisher
American Association for Cancer Research (AACR)
Citation
Hoang, Trish T. et al. "A Human Ribonuclease Variant and ERK-Pathway Inhibitors Exhibit Highly Synergistic Toxicity for Cancer Cells." Molecular Cancer Therapeutics 17, 12 (December 2018): 2622–2632 © 2018 American Association for Cancer Research
Version
Author's final manuscript
Abstract
Pancreatic-type ribonucleases (ptRNases) are prevalent secretory enzymes that catalyze the cleavage of RNA. Ribonuclease inhibitor (RI) is a cytosolic protein that has femtomolar affinity for ptRNases, affording protection from the toxic catalytic activity of ptRNases, which can invade human cells. A human ptRNase variant that is resistant to inhibition by RI is a cytotoxin that is undergoing a clinical trial as a cancer chemotherapeutic agent. We find that the ptRNase and protein kinases in the ERK pathway exhibit strongly synergistic toxicity toward lung cancer cells (including a KRAS[superscript G12C] variant) and melanoma cells (including BRAF[superscript V600E] variants). The synergism arises from inhibiting the phosphorylation of RI and thereby diminishing its affinity for the ptRNase. These findings link seemingly unrelated cellular processes, and suggest that the use of a kinase inhibitor to unleash a cytotoxic enzyme could lead to beneficial manifestations in the clinic.
MIT Department
Massachusetts Institute of Technology. Department of Chemistry
Terms of Use
Creative Commons Attribution-Noncommercial-Share Alike
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DOI of Published Version
https://doi.org/10.1158/1535-7163.mct-18-0724
