Redifferentiation of iodine-refractory metastatic thyroid cancer: from bench to bedside, through a network analysis

BACKGROUND: Radioiodine-refractory (RAIR) differentiated thyroid cancers (DTC) lose the ability to efficiently concentrate iodide, rendering RAI (iodine-131; I-131) ineffective. Few studies have shown improved RAI uptake after MEK inhibitors (MEKi) and/or BRAF inhibitors (BRAFi). MicroRNA (miRNA) role in redifferentiation process has been poorly investigated. METHODS: We retrospectively evaluated RAIR DTC patients treated with redifferentiation therapy using kinase inhibitor (KI) therapy with single-agent or combination MEKi and/or BRAFi. Our primary objectives were the percentage of patients with uptake on diagnostic (Dx) and post-treatment (post-Tx) whole body scan (WBS), and the radiologic response to I-131 achieved over that seen with KI. We exploited a bioinformatic approach (SWItchMiner, SWIM) to identify the key genes (switch genes) involved in BRAF-mediated carcinogenesis. MicroRNA Enrichment TURned NETwork (Mienturnet) was used to find the most important miRNAs able to regulate these switch genes. We validated our results by in vitro experiments. RESULTS: A total of 41 patients with RAIR, advanced DTC (76% BRAF V600E mutant cancer) were included in the study. At post treatment scan, there was uptake, either optimal or suboptimal, in 95% of patients. After I-131, 73% of patients were deemed treatment successes, reaching stable or partial response, that lasted at least one year without treatment on systemic therapy. The median PFS was 29 months from the start of KI and the median TTP was 20 months from RAI administration. The investigation of mutational landscape of BRAF mutated papillaty thiroid cancer (PTC) by SWIM allowed to identify a subset of switch genes (227), 30% of which is regulated by hsa-miR-335-5p. In vitro experiments showed that miRNA-335-5p is lost in primary or continuous BRAF mutated cell lines. Its over-expression in thyroid tumor cell lines harboring BRAF mutation induces the activation of NIS protein and increases intra-cellular iodide uptake. CONCLUSIONS: Redifferentiation therapy with MEKi and/or BRAFi resensitizes a subset of RAIR DTC patients to RAI and may result in prolonged stable disease off KI. Hsa-miR-335-5p may have a role in redifferentiation of RAIR BRAF-mutated papillary thyroid cancer. MiR-335-5p over-expression may contribute to restoring RAI responsiveness.