Hilhorst Riet, van den Berg Adrienne, Boender Piet, van Wezel Tom, Kievits Tim, de Wijn Rik, Ruijtenbeek Rob, Corver Willem E, Morreau Hans
PamGene International BV, 5211 HH 's-Hertogenbosch, The Netherlands.
Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
Cancers (Basel). 2023 Sep 8;15(18):4477. doi: 10.3390/cancers15184477.
Differentiated non-medullary thyroid cancer (NMTC) can be effectively treated by surgery followed by radioactive iodide therapy. However, a small subset of patients shows recurrence due to a loss of iodide transport, a phenotype frequently associated with BRAF V600E mutations. In theory, this should enable the use of existing targeted therapies specifically designed for BRAF V600E mutations. However, in practice, generic or specific drugs aimed at molecular targets identified by next generation sequencing (NGS) are not always beneficial. Detailed kinase profiling may provide additional information to help improve therapy success rates. In this study, we therefore investigated whether serine/threonine kinase (STK) activity profiling can accurately classify benign thyroid lesions and NMTC. We also determined whether dabrafenib (BRAF V600E-specific inhibitor), as well as sorafenib and regorafenib (RAF inhibitors), can differentiate BRAF V600E from non-BRAF V600E thyroid tumors. Using 21 benign and 34 malignant frozen thyroid tumor samples, we analyzed serine/threonine kinase activity using PamChippeptide microarrays. An STK kinase activity classifier successfully differentiated malignant (26/34; 76%) from benign tumors (16/21; 76%). Of the kinases analyzed, PKC (theta) and PKD1 in particular, showed differential activity in benign and malignant tumors, while oncocytic neoplasia or Graves' disease contributed to erroneous classifications. Ex vivo BRAF V600E-specific dabrafenib kinase inhibition identified 6/92 analyzed peptides, capable of differentiating BRAF V600E-mutant from non-BRAF V600E papillary thyroid cancers (PTCs), an effect not seen with the generic inhibitors sorafenib and regorafenib. In conclusion, STK activity profiling differentiates benign from malignant thyroid tumors and generates unbiased hypotheses regarding differentially active kinases. This approach can serve as a model to select novel kinase inhibitors based on tissue analysis of recurrent thyroid and other cancers.
分化型非髓样甲状腺癌（NMTC）可通过手术加放射性碘治疗得到有效治疗。然而，一小部分患者会因碘转运丧失而复发，这种表型常与BRAF V600E突变相关。理论上，这应该能够使用专门针对BRAF V600E突变设计的现有靶向疗法。然而，在实践中，针对下一代测序（NGS）鉴定出的分子靶点的通用或特异性药物并不总是有益的。详细的激酶分析可能会提供额外信息，以帮助提高治疗成功率。因此，在本研究中，我们调查了丝氨酸/苏氨酸激酶（STK）活性分析是否能准确区分良性甲状腺病变和NMTC。我们还确定了达拉非尼（BRAF V600E特异性抑制剂）以及索拉非尼和瑞戈非尼（RAF抑制剂）是否能区分BRAF V600E与非BRAF V600E甲状腺肿瘤。我们使用21个良性和34个恶性冷冻甲状腺肿瘤样本，通过PamChippeptide微阵列分析丝氨酸/苏氨酸激酶活性。一种STK激酶活性分类器成功区分了恶性肿瘤（26/34；76%）和良性肿瘤（16/21；76%）。在所分析的激酶中，特别是蛋白激酶C（θ）和蛋白激酶D1在良性和恶性肿瘤中表现出不同的活性，而嗜酸细胞瘤或格雷夫斯病会导致错误分类。体外BRAF V600E特异性达拉非尼激酶抑制鉴定出6/92个分析肽，能够区分BRAF V600E突变型和非BRAF V600E乳头状甲状腺癌（PTC），而通用抑制剂索拉非尼和瑞戈非尼未观察到这种效果。总之，STK活性分析可区分良性和恶性甲状腺肿瘤，并产生关于差异活性激酶的无偏假设。这种方法可作为基于复发性甲状腺癌和其他癌症组织分析选择新型激酶抑制剂的模型。
