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在BRAF突变结直肠癌中,LSD1抑制减弱了向治疗诱导的血统可塑性

Christopher A Ladaika^1,2,3, Averi Chakraborty^2,4, Ashiq Masood^3,5

¹Genome, Cell, and Developmental Biology Graduate Program, Department of Biology, Indiana University Bloomington, Bloomington, IN, 47405, USA.

Molecular cancer

|April 23, 2025

概括

针对BRAF V600E结肠直肠癌 (CRC) 的向治疗可以导致血统可塑性,丰富肠内分泌细胞 (EECs). 抑制LSD1阻断了这种抗药性机制,可能改善CRC患者的治疗结果.

科学领域:

在瘤学瘤学.
分子生物学分子生物学
癌症研究癌症研究

背景情况:

在10%的转移性结直肠癌 (CRC) 中发现了BRAF激活突变,与更差的预后和减少对化疗反应相关.
BRAF V600E CRC 患者经常接受 BRAF 和 EGFR 抑制剂,最近批准了在未经治疗的情况下进行组合治疗.
血统可塑性,特别是神经内分泌癌,是向癌症治疗中的新兴抵抗机制,肠内分泌细胞 (EEC) 独特地存在于BRAF突变的CRC.

研究的目的:

研究BRAF和EGFR抑制剂治疗对BRAF突变结直肠癌模型中的细胞组成的影响.
确定是否抑制氨酸脱甲基酶LSD1可以防止向治疗诱导的谱系可塑性.

主要方法:

利用基因表达,成像和单细胞分析来评估在BRAF突变CRC模型中BRAF加EGFR抑制剂治疗后细胞组成的变化.
选了多种临床相关的LSD1抑制剂,以确定阻断治疗诱导的细胞组成变化的有效性.

主要成果:

结合BRAF和EGFR抑制在所有测试的BRAF突变CRC模型中对EECs进行了一致的丰富.
一组BRAF V600E CRC患者样本的子集在向治疗后显示了EEC和其他分泌细胞类型的丰富.
用临床抑制剂抑制LSD1有效地通过破坏LSD1,CoREST2和STAT3相互作用来减弱针对性治疗诱导的EEC丰富.

结论:

在BRAF V600E CRC中,BRAF加EGFR抑制会诱导血统可塑性,这代表了一种新的抵抗机制.
抑制LSD1表明有可能克服这种治疗诱导的耐药性,并改善BRAF V600E CRC.患者的治疗反应.

关键词:

这就是BRAF.这种药物是Cetuximab.结肠直肠癌是一种癌症.这是Encorafenib.一个LSD1一个LSD1 血统的可塑性血统的可塑性神经内分泌的神经内分泌

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