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A genome-wide CRISPR screen identifies FBXO42 involvement in resistance toward MEK inhibition in NRAS-mutant melanoma.
- Source :
-
Pigment cell & melanoma research [Pigment Cell Melanoma Res] 2020 Mar; Vol. 33 (2), pp. 334-344. Date of Electronic Publication: 2019 Oct 10. - Publication Year :
- 2020
-
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.<br /> (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Subjects :
- Base Sequence
Biomarkers, Tumor genetics
Biomarkers, Tumor metabolism
CRISPR-Cas Systems genetics
Cell Line, Tumor
Genetic Testing
Humans
MAP Kinase Kinase Kinases metabolism
MAP Kinase Signaling System drug effects
MAP Kinase Signaling System genetics
Melanoma drug therapy
Mitogen-Activated Protein Kinase Kinases antagonists & inhibitors
Models, Biological
Mutation genetics
Protein Binding drug effects
Protein Kinase Inhibitors pharmacology
Protein Kinase Inhibitors therapeutic use
Pyridones pharmacology
Pyridones therapeutic use
Pyrimidinones pharmacology
Pyrimidinones therapeutic use
Skin Neoplasms drug therapy
Drug Resistance, Neoplasm genetics
F-Box Proteins genetics
F-Box Proteins metabolism
GTP Phosphohydrolases genetics
Genome, Human
Melanoma genetics
Membrane Proteins genetics
Skin Neoplasms genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1755-148X
- Volume :
- 33
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Pigment cell & melanoma research
- Publication Type :
- Academic Journal
- Accession number :
- 31549767
- Full Text :
- https://doi.org/10.1111/pcmr.12825