SPRED1 deletion confers resistance to MAPK inhibition in melanoma.
Adaptor Proteins, Signal Transducing
/ genetics
Animals
Cell Line, Tumor
Cell Proliferation
/ drug effects
Down-Regulation
/ drug effects
Drug Resistance, Neoplasm
/ drug effects
Gene Deletion
Humans
MAP Kinase Signaling System
/ drug effects
Melanoma
/ enzymology
Protein Kinase Inhibitors
/ pharmacology
Proto-Oncogene Proteins B-raf
/ antagonists & inhibitors
Skin Neoplasms
/ enzymology
Tumor Suppressor Protein p53
/ metabolism
Zebrafish
Journal
The Journal of experimental medicine
ISSN: 1540-9538
Titre abrégé: J Exp Med
Pays: United States
ID NLM: 2985109R
Informations de publication
Date de publication:
01 03 2021
01 03 2021
Historique:
received:
28
05
2020
revised:
12
10
2020
accepted:
06
11
2020
entrez:
11
12
2020
pubmed:
12
12
2020
medline:
15
9
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33306107
pii: 211585
doi: 10.1084/jem.20201097
pmc: PMC7927430
pii:
doi:
Substances chimiques
Adaptor Proteins, Signal Transducing
0
Protein Kinase Inhibitors
0
SPRED1 protein, human
0
Tumor Suppressor Protein p53
0
Proto-Oncogene Proteins B-raf
EC 2.7.11.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NCI NIH HHS
ID : R21 CA215910
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA176111
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA103846
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016042
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA163222
Pays : United States
Informations de copyright
© 2020 Ablain et al.
Déclaration de conflit d'intérêts
Disclosures: R.S. Lo reported grants from Pfizer, Merck, OncoSec, and BMS outside the submitted work. L.I. Zon reported personal fees from Scholar Rock Inc., Fate Therapeutics, CAMP4 Therapeutics, Amagma Therapeutics, Celularity, and Cellarity outside the submitted work. No other disclosures were reported.
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