The activation of NF‑kB and expression of RET/TC in the TC group were significantly increased (P<0.05) and were correlated with the protein expression of Ku80 (P<0.05).
This includes frequently reported gene fusions such as CCDC6/RET (PTC1), PRKAR1A/RET (PTC2) and ETV6/NTRK3 , and gene fusions that are less common in thyroid cancer (TPM3/NTRK1, EML4/ALK and EML4/NTRK3).
While RET TK inhibitors (TKIs) are used to treat thyroid cancer and are in clinical trials for RET fusion-positive non-small cell lung cancer, the impact of mutations in the RET kinase domain on drug sensitivity is largely uncharacterized.
Furthermore, our KDR gene fusion network analysis revealed six of the seven kinases with the highest DoF scores (ALK, BRAF, MET, NTRK1, NTRK3 and RET) were all observed in thyroid carcinoma.
Several multikinase inhibitors with activity against RET have been explored in the clinic, and confirmed responses to targeted therapy with these agents have been observed in patients with RET-rearranged lung cancers or RET-mutant thyroid cancers.
Several drugs targeting RET have been approved by the FDA for the treatment of cancer: (i) cabozantinib and vandetanib for medullary thyroid carcinomas and (ii) lenvatinib and sorafenib for differentiated thyroid cancers.
These results confirm that PATZ1 downregulation has a critical role in thyroid carcinogenesis, showing that it cooperates with RET/PTC1 in thyroid cancer progression.
<i>In vivo</i>, BLU-667 potently inhibited growth of NSCLC and thyroid cancer xenografts driven by various <i>RET</i> mutations and fusions without inhibiting VEGFR2.
In the present study, we investigated whether the oncogenic RET mutants RET2A (C634R) and RET2B (M918T) were regulated by LRIG1, and the possible effects of LRIG1 expression in thyroid cancer were investigated in three different clinical cohorts and in a RET2B-driven mouse model of MTC.
Although the mechanisms of cellular injury and repair resulting from ionizing radiation are well described, the genomics of radiation-induced tumours are still relatively poorly understood, with some exceptions, such as RET rearrangement in thyroid carcinomas following iodine-131 exposure and MYC amplification in cutaneous angiosarcoma following chest wall irradiation for breast cancer.
To assess the therapeutic potential of AL3810 in treating thyroid cancer involving RET gene fusion, we showed that AL3810 (1-10 μmol/L) dose-dependently inhibited the proliferation of RET-driven Baf3 cell line Baf3-CCDC6-RET, and the auto-phosphorylation of RET in these cells.
Dysregulated activation of RET kinase, either through point mutations or gene fusions, is accountable for a significant fraction of thyroid carcinomas, as well as a minor population of lung cancers.
These data provide the first evidence of a direct link between IDO1 expression and the oncogenic activation of RET in thyroid carcinoma and describe the involved signal transduction pathways.
We evaluated the best tagging SNPs from our previous PTC study and additionally included SNPs in or near FOXE1 and NKX2-1 genes, known susceptibility loci for thyroid cancer.