Darabi Sourat, Stafford Phillip, Braxton David R, Zuazo Carlos E, Brodie Taylor J, Demeure Michael J
Hoag Family Cancer Institute, Newport Beach, CA 92663, USA.
School of Life Sciences, Arizona State University, Tempe, AZ 85287, USA.
Int J Mol Sci. 2025 Aug 16;26(16):7910. doi: 10.3390/ijms26167910.
BRAF inhibitors have a 50-70% response rate in melanoma but are less effective for thyroid cancer. Differential response may be from activation or expression of downstream mitogen-activated protein kinase (MAPK) pathway genes. Retrospective analysis compared whole exome and transcriptome sequencing in melanoma and thyroid cancers from April 2019 to October 2023. The MAPK Activation Score (MPAS) was calculated using Z-score normalized/log-transformed values indicating expression across 10 MAPK-associated genes. Our tumor registry provided outcome data. V600E mutations were identified in 33 of 200 (17%) melanomas and 14 (7%) had other mutations (V600K/R). Of 49 thyroid tumor samples, V600E mutations were found in 19 (39%). RNA expression of BRAF and the 10 MAPK-associated genes were increased in melanomas with V600E compared to wild-type ( = 0.02). Conversely, V600E mutation in thyroid cancer was not associated with increased expression nor MAPK pathway activation. No significant difference in overall survival based on mutation was observed in the subset of patients where data was available. The MAPK pathway is differentially affected by the different cancers, with increased MAPK activation observed in melanoma and not in thyroid cancer. This may account in part for the observed differential response to BRAF inhibitors.
BRAF抑制剂在黑色素瘤中的应答率为50%-70%，但对甲状腺癌的疗效较差。不同的应答可能源于下游丝裂原活化蛋白激酶（MAPK）通路基因的激活或表达。回顾性分析比较了2019年4月至2023年10月黑色素瘤和甲状腺癌的全外显子组和转录组测序。使用Z分数标准化/对数转换值计算MAPK激活评分（MPAS），该值表示10个MAPK相关基因的表达情况。我们的肿瘤登记处提供了结局数据。在200例黑色素瘤中有33例（17%）检测到V600E突变，14例（7%）有其他突变（V600K/R）。在49例甲状腺肿瘤样本中，19例（39%）发现V600E突变。与野生型相比，V600E黑色素瘤中BRAF和10个MAPK相关基因的RNA表达增加（P = 0.02）。相反，甲状腺癌中的V600E突变与表达增加或MAPK通路激活无关。在有数据的患者亚组中，未观察到基于突变的总生存期有显著差异。不同癌症对MAPK通路的影响不同，黑色素瘤中观察到MAPK激活增加，而甲状腺癌中未观察到。这可能部分解释了观察到的对BRAF抑制剂的不同应答。
