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

Abstract

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.

The Effects of Tetrahydrocurcumin on Adriamycin and Taxane resistance in Anaplastic Thyroid Cancer Cells

“…Some targeting agents, such as dabrafenib and trametinib, have been added in order to enhance chemotherapy e cacy and overcome drug resistance (16, 40). However, ATC cells eventually develop resistance to targeted therapies and tyrosine kinase inhibitors, similar to classical cytostatics (26,41). As the authors of this study, we believed that targeting ATC stem cells (CSCs) was the most effective approach to increasing chemotherapy e cacy by suppressing drug resistance mechanisms.…”

Ruxolitinib induces apoptosis and pyroptosis of anaplastic thyroid cancer via the transcriptional inhibition of DRP1-mediated mitochondrial fission

“…Wholegenome sequencing and whole-exome sequencing analysis of ATC have shown that JAK2/3-STAT1/2 mRNA levels are highly upregulated in ATC, suggesting an overactivated state of JAK2/3-STAT1/2 [47]. JAK1/2-STAT1/3 is compensatorily upregulated under the intervention of BRAF V600E inhibitors and is involved in developing drug resistance in BRAF V600E ATC [48]. Surprisingly, it appears that the analysis of JAK1/2-STAT3, along with their phosphorylated forms, within ATC patient tumor tissues has been relatively infrequent.…”

Recent advances in anaplastic thyroid cancer management

“…All these phenomena lead to bypass of the BRAF inhibition and promote reactivation of the MAPK pathway as well as tumor growth. Recently, Limberg et al [44 ▪ ] demonstrated increased activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway in resistant BRAFV600E -mutated clones after treatment with the BRAF inhibitor vemurafenib and achieved significant control of cancer cell growth after inhibition of the JAK/STAT pathway in these cells. This suggests that the JAK/STAT signaling pathway might be a potential therapeutic target to overcome acquired resistance to BRAF inhibitors.…”