PUBLICATION
SPRED1 deletion confers resistance to MAPK inhibition in melanoma
- Authors
- Ablain, J., Liu, S., Moriceau, G., Lo, R.S., Zon, L.I.
- ID
- ZDB-PUB-201212-35
- Date
- 2021
- Source
- The Journal of experimental medicine 218(3): (Journal)
- Registered Authors
- Zon, Leonard I.
- Keywords
- none
- MeSH Terms
-
- Adaptor Proteins, Signal Transducing/genetics*
- Animals
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Down-Regulation/drug effects
- Drug Resistance, Neoplasm/drug effects
- Drug Resistance, Neoplasm/genetics*
- Gene Deletion*
- Humans
- MAP Kinase Signaling System*/drug effects
- Melanoma/enzymology*
- Melanoma/genetics*
- Melanoma/pathology
- Protein Kinase Inhibitors/pharmacology*
- Proto-Oncogene Proteins B-raf/antagonists & inhibitors
- Proto-Oncogene Proteins B-raf/metabolism
- Skin Neoplasms/enzymology
- Skin Neoplasms/genetics
- Skin Neoplasms/pathology
- Tumor Suppressor Protein p53/metabolism
- Zebrafish
- PubMed
- 33306107 Full text @ J. Exp. Med.
Citation
Ablain, J., Liu, S., Moriceau, G., Lo, R.S., Zon, L.I. (2021) SPRED1 deletion confers resistance to MAPK inhibition in melanoma. The Journal of experimental medicine. 218(3):.
Abstract
Functional evaluation of genetic lesions can discover a role in cancer initiation and progression and help develop novel therapeutic strategies. We previously identified the negative MAPK regulator SPRED1 as a novel tumor suppressor in KIT-driven melanoma. Here, we show that SPRED1 is also frequently deleted in human melanoma driven by mutant BRAF. We found that SPRED1 inactivation in human melanoma cell lines and primary zebrafish melanoma conferred resistance to BRAFV600E inhibition in vitro and in vivo. Mechanistically, SPRED1 loss promoted melanoma cell proliferation under mutant BRAF inhibition by reactivating MAPK activity. Consistently, biallelic deletion of SPRED1 was observed in a patient whose melanoma acquired resistance to MAPK-targeted therapy. These studies combining work in human cells and in vivo modeling in zebrafish demonstrate a new mechanism of resistance to BRAFV600E inhibition in melanoma.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping