Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, USA.
University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, CO, USA.
Cancer Biol Ther. 2024 Dec 31;25(1):2332000. doi: 10.1080/15384047.2024.2332000. Epub 2024 Mar 23.
Thyroid cancer is one of the deadliest endocrine cancers, and its incidence has been increasing. While mutations in are common in thyroid cancer, advanced PTC patients currently lack therapeutic options targeting the MAPK pathway, and despite the approved combination of BRAF and MEK1/2 inhibition for mutant ATC, resistance often occurs. Here, we assess growth and signaling responses to combined BRAF and MEK1/2 inhibition in a panel of mutant thyroid cancer cell lines. We first showed that combined BRAF and MEK1/2 inhibition synergistically inhibits cell growth in four out of six of the --mutant thyroid cancer cell lines tested. Western blotting showed that the MAPK pathway was robustly inhibited in all cell lines. Therefore, to identify potential mechanisms of resistance, we performed RNA-sequencing in cells sensitive or resistant to MEK1/2 inhibition. In response to MEK1/2 inhibition, we identified a downregulation of Aurora Kinase B (AURKB) in sensitive but not resistant cells. We further demonstrated that combined MEK1/2 and AURKB inhibition slowed cell growth, which was phenocopied by inhibiting AURKB and ERK1/2. Finally, we show that combined AURKB and ERK1/2 inhibition induces apoptosis in mutant thyroid cancer cell lines, together suggesting a potential combination therapy for -mutant thyroid cancer patients.
甲状腺癌是最致命的内分泌癌之一，其发病率一直在上升。虽然 中的突变在甲状腺癌中很常见，但晚期 PTC 患者目前缺乏针对 MAPK 通路的治疗选择，尽管 BRAF 和 MEK1/2 抑制剂的联合治疗已被批准用于突变型 ATC，但耐药性经常发生。在这里，我们评估了一组突变型甲状腺癌细胞系中联合 BRAF 和 MEK1/2 抑制的生长和信号转导反应。我们首先表明，在六种测试的 --突变甲状腺癌细胞系中，有四种细胞系中联合 BRAF 和 MEK1/2 抑制协同抑制细胞生长。Western blot 显示 MAPK 通路在所有细胞系中均被强烈抑制。因此，为了确定潜在的耐药机制，我们在对 MEK1/2 抑制敏感或耐药的细胞中进行了 RNA-seq 分析。对 MEK1/2 抑制的反应中，我们发现 AURKB（Aurora 激酶 B）在敏感细胞中下调，但在耐药细胞中没有下调。我们进一步证明，联合 MEK1/2 和 AURKB 抑制减缓了细胞生长，这与抑制 AURKB 和 ERK1/2 的作用相似。最后，我们表明联合 AURKB 和 ERK1/2 抑制诱导突变型甲状腺癌细胞系凋亡，共同提示对 --突变甲状腺癌患者有潜在的联合治疗方法。
