Abstract
Clinical efficacy of differentiation therapy with mitogen‐activated protein kinase inhibitors (MAPKi) for lethal radioiodine‐refractory papillary thyroid cancer (RR‐PTC) urgently needs to be improved and the aberrant trimethylation of histone H3 lysine 27 (H3K27) plays a vital role in BRAF V600E‐MAPK‐induced cancer dedifferentiation and drug resistance. Therefore, dual inhibition of MAPK and histone methyltransferase (EZH2) may produce more favourable treatment effects. In this study, BRAF V600E‐mutant (BCPAP and K1) and BRAF‐wild‐type (TPC‐1) PTC cells were treated with MAPKi (dabrafenib or selumetinib) or EZH2 inhibitor (tazemetostat), or in combination, and the expression of iodine‐metabolizing genes, radioiodine uptake, and toxicity were tested. We found that tazemetostat alone slightly increased iodine‐metabolizing gene expression and promoted radioiodine uptake and toxicity, irrespective of the BRAF status. However, MAPKi induced these effects preferentially in BRAF V600E mutant cells, which was robustly strengthened by tazemetostat incorporation. Mechanically, MAPKi‐induced decrease of trimethylation of H3K27 was evidently intensified by tazemetostat in BRAF V600E‐mutant cells. In conclusion, tazemetostat combined with MAPKi enhances differentiation of PTC cells harbouring BRAF V600E through synergistically decreasing global trimethylation of H3K27, representing a novel differentiation strategy.
Highlights
True increases in the global occurrence of thyroid cancer have been reported recently, owing to a steady rise in the incidence of papillary thyroid cancer (PTC), which accounts for approximately 85% of all thyroid cancers.1-3 131I therapy is a conventional and effective treatment for unresectable disease, which is based on the nature of radioiodine avidity of tumour originating from thyroid follicular cells via the sodium/iodide symporter (NIS)
A major mechanism underlying the development of refractory papillary thyroid cancer (RR-PTC) is the aberrant silencing of iodine-metabolizing genes such as Nis, Tshr, Tg and Tpo, which is a result of BRAFV600E mutation-induced activation of the mitogen-activated protein kinase (MAPK) pathway.[4]
RR-PTC represents a major therapeutic challenge in thyroid cancer medicine, which is mainly caused by BRAFV600E mutation that leads to the abnormal activation of MAPK pathway.[21,22]
Summary
True increases in the global occurrence of thyroid cancer have been reported recently, owing to a steady rise in the incidence of papillary thyroid cancer (PTC), which accounts for approximately 85% of all thyroid cancers.1-3 131I therapy is a conventional and effective treatment for unresectable disease, which is based on the nature of radioiodine avidity of tumour originating from thyroid follicular cells via the sodium/iodide symporter (NIS). Increasing evidences, including our previous study, have demonstrated that MAPK inhibitors (MAPKi) can induce differentiation in thyroid cancer[5,6]; their clinical effectiveness in restoring 131I uptake remains insufficient.[7,8,9,10] Thought-provokingly, reinduction of 131I uptake in DTC patients treated with sorafenib failed even in vitro study had showed promising data.[7] Besides, the BRAFV600E inhibitor dabrafenib restored new radioiodine uptake in 60% of 10 patients, but the objective response rate was only 20%.8. The clinically tested MEK inhibitor selumetinib had shown promising differentiation efficacy, it seemed to be less effective in thyroid cancers with a BRAF mutation.[9] the differentiation effect of MAPK inhibitors remains to be improved, so that 131I may sufficiently exert its theranostics actions. We conceived this study to evaluate the differentiation efficacy of EZH2 inhibitor, assess the impact on differentiation induced by EZH2 inhibitor combined with MAPKi and elucidate the underlying mechanisms in PTC cell lines
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