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

Mol Cancer Ther. 2018 Dec;17(12):2622-2632. doi: 10.1158/1535-7163.MCT-18-0724. Epub 2018 Oct 3.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 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
  • Mitogen-Activated Protein Kinase Kinases / metabolism
  • Models, Biological
  • Mutation / genetics*
  • Neoplasms / pathology*
  • Phosphorylation / drug effects
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / toxicity*
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors
  • Proto-Oncogene Proteins B-raf / metabolism
  • Proto-Oncogene Proteins p21(ras) / antagonists & inhibitors
  • Ribonucleases / antagonists & inhibitors*
  • Ribonucleases / genetics*
  • Substrate Specificity / drug effects

Substances

  • 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)