Activation of the JAK/STAT Pathway Leads to BRAF Inhibitor Resistance in BRAFV600E Positive Thyroid Carcinoma

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 ever, the results have been disappointing in thyroid cancers compared with BRAFV600E melanoma, as thyroid cancers quickly 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 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 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.

Automated summary

A subset of thyroid cancers, including recurrent differentiated thyroid cancers and anaplastic thyroid cancer (ATC), are difficult to treat with current methods. A study found that the BRAFV600E mutation, while effective in melanoma, only showed temporary activation of the molecular pathway in thyroid cancer cells. However, further analysis revealed that the JAK/STAT pathway is significantly activated in response to BRAFi and is associated with recurrence and prognosis in thyroid cancer patients.