A Human Ribonuclease Variant and ERK-Pathway Inhibitors Exhibit Highly Synergistic Toxicity for Cancer Cells
Author(s)
Hoang, Trish T.; Tanrikulu, Ismet Caglar; Vatland, Quinn A.; Hoang, Trieu M.; Raines, Ronald T![Thumbnail](/bitstream/handle/1721.1/123520/nihms-1508948.pdf.jpg?sequence=4&isAllowed=y)
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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.
Date issued
2018-12Department
Massachusetts Institute of Technology. Department of ChemistryJournal
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
ISSN
1535-7163
1538-8514