Activation of the JAK/STAT Pathway Leads to BRAF Inhibitor Resistance in BRAFV600E Positive Thyroid Carcinoma.
Humans
Proto-Oncogene Proteins B-raf
/ metabolism
Janus Kinases
/ genetics
Sulfonamides
/ pharmacology
Signal Transduction
STAT Transcription Factors
/ genetics
Neoplasm Recurrence, Local
/ drug therapy
Thyroid Neoplasms
/ drug therapy
Protein Kinase Inhibitors
/ pharmacology
Thyroid Carcinoma, Anaplastic
/ drug therapy
Mutation
RNA
Drug Resistance, Neoplasm
/ genetics
Cell Line, Tumor
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:
01 05 2023
01 05 2023
Historique:
received:
05
10
2021
revised:
25
03
2022
accepted:
11
01
2023
medline:
2
5
2023
pubmed:
16
2
2023
entrez:
15
2
2023
Statut:
ppublish
Résumé
A subset of thyroid cancers, recurrent differentiated thyroid cancers and anaplastic thyroid cancer (ATC), are difficult to treat by thyroidectomy and systemic therapy. A common mutation in thyroid cancer, BRAFV600E, has targetable treatment options; however, the results have been disappointing in thyroid cancers compared with BRAFV600E melanoma, as thyroid cancers quickly become resistant to BRAFV600E inhibitor (BRAFi). Here, we studied the molecular pathway that is induced in BRAFV600E thyroid cancer cells and patient-derived tumor samples in response to BRAFi, vemurafenib, using RNA-sequencing and molecular analysis. Both inducible response to BRAFi and acquired BRAFi resistance in BRAFV600E thyroid cancer cells showed significant activation of the JAK/STAT pathway. Functional analyses revealed that the combination of BRAFi and inhibitors of JAK/STAT pathway controlled BRAFV600E thyroid cancer cell growth. The Cancer Genome Atlas data analysis demonstrated that potent activation of the JAK/STAT signaling was associated with shorter recurrence rate in patients with differentiated thyroid cancer. Analysis of tumor RNA expression in patients with poorly differentiated thyroid cancer and ATC also support that enhanced activity of JAK/STAT signaling pathway is correlated with worse prognosis. Our study demonstrates that JAK/STAT pathway is activated as BRAFV600E thyroid cancer cells develop resistance to BRAFi and that this pathway is a potential target for anticancer activity and to overcome drug resistance that commonly develops to treatment with BRAFi in thyroid cancer. Dual inhibition of BRAF and JAK/STAT signaling pathway is a potential therapeutic treatment for anticancer activity and to overcome drug resistance to BRAFi in thyroid cancer.
Identifiants
pubmed: 36790391
pii: 716575
doi: 10.1158/1541-7786.MCR-21-0832
pmc: PMC10159921
mid: NIHMS1867166
doi:
Substances chimiques
Proto-Oncogene Proteins B-raf
EC 2.7.11.1
Janus Kinases
EC 2.7.10.2
Sulfonamides
0
STAT Transcription Factors
0
Protein Kinase Inhibitors
0
RNA
63231-63-0
BRAF protein, human
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
Pagination
397-410Subventions
Organisme : NCI NIH HHS
ID : R01 CA217059
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA254035
Pays : United States
Informations de copyright
©2023 American Association for Cancer Research.
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