TY - JOUR
T1 - Activation of the JAK/STAT Pathway Leads to BRAF Inhibitor Resistance in BRAFV600E Positive Thyroid Carcinoma
AU - Limberg, Jessica
AU - Egan, Caitlin E.
AU - Gray, Katherine D.
AU - Singh, Mandeep
AU - Loewenstein, Zachary
AU - Yang, Yanping
AU - Riascos, Maria Cristina
AU - Asadi, Hala Al
AU - Safe, Parima
AU - Eshaky, Steve El
AU - Liang, Heng
AU - Ullmann, Timothy M.
AU - Wang, Weibin
AU - Li, Wei
AU - Zhang, Tuo
AU - Xiang, Jenny
AU - Stefanova, Dessislava
AU - Jin, Moonsoo M.
AU - Zarnegar, Rasa
AU - Fahey, Thomas J.
AU - Min, Irene M.
N1 - Funding Information:
The authors acknowledge the support of the Weill Cornell Medicine Facilities: Genomics Resource Core and Flow Cytometer Core. The results here are in part based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga. The research was supported by the Emerson Collective Cancer Research Fund (ECCRF 191824–01; to I.M. Min) and NIH NCI (R01CA217059 and R01CA254035; to M.M. Jin).
Publisher Copyright:
© 2023 American Association for Cancer Research.
PY - 2023/5/1
Y1 - 2023/5/1
N2 - UNLABELLED: 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.IMPLICATIONS: 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.
AB - UNLABELLED: 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.IMPLICATIONS: 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.
KW - Humans
KW - Proto-Oncogene Proteins B-raf/metabolism
KW - Janus Kinases/genetics
KW - Sulfonamides/pharmacology
KW - Signal Transduction
KW - STAT Transcription Factors/genetics
KW - Neoplasm Recurrence, Local/drug therapy
KW - Thyroid Neoplasms/drug therapy
KW - Protein Kinase Inhibitors/pharmacology
KW - Thyroid Carcinoma, Anaplastic/drug therapy
KW - Mutation
KW - RNA
KW - Drug Resistance, Neoplasm/genetics
KW - Cell Line, Tumor
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UR - http://www.scopus.com/inward/citedby.url?scp=85159247116&partnerID=8YFLogxK
U2 - 10.1158/1541-7786.MCR-21-0832
DO - 10.1158/1541-7786.MCR-21-0832
M3 - Article
C2 - 36790391
AN - SCOPUS:85159247116
SN - 1541-7786
VL - 21
SP - 397
EP - 410
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 5
ER -