dc.contributor.author | Hoang, Trish T. | |
dc.contributor.author | Tanrikulu, Ismet Caglar | |
dc.contributor.author | Vatland, Quinn A. | |
dc.contributor.author | Hoang, Trieu M. | |
dc.contributor.author | Raines, Ronald T | |
dc.date.accessioned | 2020-01-22T15:52:37Z | |
dc.date.available | 2020-01-22T15:52:37Z | |
dc.date.issued | 2018-12 | |
dc.identifier.issn | 1535-7163 | |
dc.identifier.issn | 1538-8514 | |
dc.identifier.uri | https://hdl.handle.net/1721.1/123520 | |
dc.description.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. | en_US |
dc.description.sponsorship | National Institutes of Health (U.S.) (Grant R01 CA073808) | en_US |
dc.language.iso | en | |
dc.publisher | American Association for Cancer Research (AACR) | en_US |
dc.relation.isversionof | http://dx.doi.org/10.1158/1535-7163.mct-18-0724 | en_US |
dc.rights | Creative Commons Attribution-Noncommercial-Share Alike | en_US |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-sa/4.0/ | en_US |
dc.source | PMC | en_US |
dc.title | A Human Ribonuclease Variant and ERK-Pathway Inhibitors Exhibit Highly Synergistic Toxicity for Cancer Cells | en_US |
dc.type | Article | en_US |
dc.identifier.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 | en_US |
dc.contributor.department | Massachusetts Institute of Technology. Department of Chemistry | en_US |
dc.relation.journal | Molecular Cancer Therapeutics | en_US |
dc.eprint.version | Author's final manuscript | en_US |
dc.type.uri | http://purl.org/eprint/type/JournalArticle | en_US |
eprint.status | http://purl.org/eprint/status/PeerReviewed | en_US |
dc.date.updated | 2020-01-06T18:23:32Z | |
dspace.date.submission | 2020-01-06T18:23:36Z | |
mit.journal.volume | 17 | en_US |
mit.journal.issue | 12 | en_US |
mit.metadata.status | Complete | |