A Human Ribonuclease Variant and ERK-Pathway Inhibitors Exhibit Highly Synergistic Toxicity for Cancer Cells.

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 KRASG12C variant) and melanoma cells (including BRAFV600E 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.

• Authors: Trish T Hoang, I Caglar Tanrikulu, Quinn A Vatland, Trieu M Hoang, Ronald T Raines
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 17 Issue 12 Pg. 2622-2632 (12 2018) ISSN: 1538-8514 [Electronic] United States
• PMID: 30282811 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• KRAS protein, human
• Protein Kinase Inhibitors
• BRAF protein, human
• Proto-Oncogene Proteins B-raf
• Mitogen-Activated Protein Kinase Kinases
• Ribonucleases
• Proto-Oncogene Proteins p21(ras)

Topics

• Cell Line, Tumor
• Cell Survival (drug effects)
• Drug Synergism
• HEK293 Cells
• Humans
• MAP Kinase Signaling System (drug effects)
• Mitogen-Activated Protein Kinase Kinases (antagonists & inhibitors, metabolism)
• Models, Biological
• Mutation (genetics)
• Neoplasms (pathology)
• Phosphorylation (drug effects)
• Protein Kinase Inhibitors (pharmacology, toxicity)
• Proto-Oncogene Proteins B-raf (antagonists & inhibitors, metabolism)
• Proto-Oncogene Proteins p21(ras) (antagonists & inhibitors)
• Ribonucleases (antagonists & inhibitors, genetics)
• Substrate Specificity (drug effects)