A genome-wide CRISPR screen identifies FBXO42 involvement in resistance toward MEK inhibition in NRAS-mutant melanoma.

Abstract

NRAS mutations are the most common alterations among RAS isoforms in cutaneous melanoma, with patients harboring these aggressive tumors having a poor prognosis and low survival rate. The main line of treatment for these patients is MAPK pathway-targeted therapies, such as MEK inhibitors, but, unfortunately, the response to these inhibitors is variable due to tumor resistance. Identifying genetic modifiers involved in resistance toward MEK-targeted therapy may assist in the development of new therapeutic strategies, enhancing treatment response and patient survival. Our whole-genome CRISPR-Cas9 knockout screen identified the target Kelch domain-containing F-Box protein 42 (FBXO42) as a factor involved in NRAS-mutant melanoma-acquired resistance to the MEK1/2 inhibitor trametinib. We further show that FBXO42, an E3 ubiquitin ligase, is involved in the TAK1 signaling pathway, possibly prompting an increase in active P38. In addition, we demonstrate that combining trametinib with the TAK1 inhibitor, takinib, is a far more efficient treatment than trametinib alone in NRAS-mutant melanoma cells. Our findings thus show a new pathway involved in NRAS-mutant melanoma resistance and provide new opportunities for novel therapeutic options.

• Authors: Adi Nagler, David W Vredevoogd, Michal Alon, Phil F Cheng, Sophie Trabish, Shelly Kalaora, Rand Arafeh, Victoria Goldin, Mitchell P Levesque, Daniel S Peeper, Yardena Samuels
• Journal: Pigment cell & melanoma research (Pigment Cell Melanoma Res) Vol. 33 Issue 2 Pg. 334-344 (03 2020) ISSN: 1755-148X [Electronic] England
• PMID: 31549767 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Chemical References

• Biomarkers, Tumor
• F-Box Proteins
• FBXO42 protein, human
• Membrane Proteins
• Protein Kinase Inhibitors
• Pyridones
• Pyrimidinones
• trametinib
• MAP Kinase Kinase Kinases
• MAP kinase kinase kinase 7
• Mitogen-Activated Protein Kinase Kinases
• GTP Phosphohydrolases
• NRAS protein, human

Topics

• Base Sequence
• Biomarkers, Tumor (genetics, metabolism)
• CRISPR-Cas Systems (genetics)
• Cell Line, Tumor
• Drug Resistance, Neoplasm (genetics)
• F-Box Proteins (genetics, metabolism)
• GTP Phosphohydrolases (genetics)
• Genetic Testing
• Genome, Human
• Humans
• MAP Kinase Kinase Kinases (metabolism)
• MAP Kinase Signaling System (drug effects, genetics)
• Melanoma (drug therapy, genetics)
• Membrane Proteins (genetics)
• Mitogen-Activated Protein Kinase Kinases (antagonists & inhibitors)
• Models, Biological
• Mutation (genetics)
• Protein Binding (drug effects)
• Protein Kinase Inhibitors (pharmacology, therapeutic use)
• Pyridones (pharmacology, therapeutic use)
• Pyrimidinones (pharmacology, therapeutic use)
• Skin Neoplasms (drug therapy, genetics)