Dasatinib Stimulates Its Own Mechanism of Resistance by Activating a CRTC3/MITF/Bcl-2 Pathway in Melanoma with Mutant or Amplified c-Kit.
Antineoplastic Agents
/ pharmacology
Apoptosis
/ drug effects
Cell Line, Tumor
Cell Proliferation
/ drug effects
Dasatinib
/ pharmacology
Drug Resistance, Neoplasm
/ drug effects
Gene Amplification
Gene Expression Regulation, Neoplastic
/ drug effects
Humans
Melanoma
/ genetics
Microphthalmia-Associated Transcription Factor
/ genetics
Mutation
Proteins
/ genetics
Proto-Oncogene Proteins c-bcl-2
/ genetics
Proto-Oncogene Proteins c-kit
/ genetics
Signal Transduction
/ drug effects
Transcription Factors
/ genetics
Journal
Molecular cancer research : MCR
ISSN: 1557-3125
Titre abrégé: Mol Cancer Res
Pays: United States
ID NLM: 101150042
Informations de publication
Date de publication:
07 2021
07 2021
Historique:
received:
09
12
2020
revised:
29
01
2021
accepted:
11
03
2021
pubmed:
21
3
2021
medline:
27
1
2022
entrez:
20
3
2021
Statut:
ppublish
Résumé
Amplification or activating mutations of c-Kit are a frequent oncogenic alteration, which occurs commonly in acral and mucosal melanoma. Among c-Kit inhibitors, dasatinib is the most active due to its ability to bind both active and inactive conformations of the receptor. However, its use as a single agent in melanoma showed limited clinical benefit. We first found that sensitivity to dasatinib is restricted to melanoma cell lines harboring c-Kit alteration but, unexpectedly, we observed lower effect at higher concentrations that can readily be found in patient blood. We then investigated relevant pathway alterations and found complete inhibition of MAPK and PI3K/AKT pathways but an increase in MITF and its downstream target Bcl-2 through CRTC3 pathway, which turn on the CREB regulated transcription of MITF. More importantly, dasatinib upregulates MITF and Bcl-2 through SIK2 inhibition revealed by CRTC3 reduced phosphorylation, CREB transcription activation of MITF, MITF transcription activation of Bcl-2 as well as pigmentation. Furthermore, overexpression of MITF renders melanoma cells resistant to all dasatinib concentrations. Selective Bcl-2 inhibition by ABT-199 or Bcl-2 knockout restores the sensitivity of melanoma cells to dasatinib, validating the involvement of MITF and Bcl-2 axis in the resistance of melanoma to dasatinib. In conclusion, we showed for the first time that dasatinib in melanoma stimulates its proper mechanism of resistance, independently of MAPK and PI3K/AKT pathways reactivation commonly associated to secondary c-Kit mutations, but through CRTC3/MITF/Bcl-2 pathway activation at clinically relevant doses which may explain the weak clinical benefit of dasatinib in patients with melanoma. IMPLICATIONS: Dasatinib stimulates its proper mechanism of resistance through CRTC3/MITF/Bcl-2 pathway, which may explain its modest clinical efficiency in patients with melanoma.
Identifiants
pubmed: 33741716
pii: 1541-7786.MCR-20-1040
doi: 10.1158/1541-7786.MCR-20-1040
doi:
Substances chimiques
Antineoplastic Agents
0
CRTC3 protein, human
0
Microphthalmia-Associated Transcription Factor
0
Proteins
0
Proto-Oncogene Proteins c-bcl-2
0
Transcription Factors
0
Proto-Oncogene Proteins c-kit
EC 2.7.10.1
Dasatinib
RBZ1571X5H
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1221-1233Informations de copyright
©2021 American Association for Cancer Research.
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