The Transcription Factor SLUG Uncouples Pancreatic Cancer Progression from the RAF-MEK1/2-ERK1/2 Pathway
The Transcription Factor SLUG Uncouples Pancreatic Cancer Progression from the RAF-MEK1/2-ERK1/2 Pathway
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DOI：
10.1158/0008-5472.can-20-4263
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发表时间：
2021-07-15
期刊：
影响因子：
11.2
通讯作者：
Arribas, Joaquin
中科院分区：
文献类型：
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作者：
Bilal, Faiz;Arenas, Enrique J.;Arribas, Joaquin
RAS或RAF的某些同工异构体的激活突变是大部分癌症的驱动因素。Raf的主要效应物MEK1/2可以被几种高度特异性的抑制剂靶向。这些抑制剂的临床活性似乎参差不齐，对突变braf驱动的肿瘤有效，但对kras驱动的肿瘤无效，如胰腺腺癌。为了提高我们对这种环境依赖性功效的理解，我们产生了对MEK1/2抑制具有抗性的胰腺癌细胞，这些细胞也对KRAS和ERK1/2抑制剂具有抗性。与亲代细胞相比，抗抑制剂细胞表现出多种表型变化，包括体内转移能力增强。转录因子SLUG可以诱导上皮细胞向间质细胞的转化，被认为是抵抗MEK1/2抑制和增加转移的关键因素。Slug，而不是类似的转录因子，预测胰腺癌患者的不良预后，并诱导细胞向细胞周期进程独立于KRASRAF-MEK1/2-ERK1/2通路的细胞表型过渡。SLUG通过两种独立的策略来靶向：(i)抑制MEK5-ERK5通路，该通路在MEK1/2抑制时负责SLUG的上调，以及（ii）直接由protac介导的降解。这两种策略在临床前胰腺癌模型中均有效，为开发更有效的胰腺癌治疗方法铺平了道路。意义：本研究表明，SLUG通过解除KRAS-RAF-MEK1/2-ERK1/2信号通路的肿瘤进展，在胰腺癌中赋予MEK1/2抑制剂耐药性，为治疗提供了新的机会。
Activating mutations in some isoforms of RAS or RAF are drivers of a substantial proportion of cancers. The main Raf effector, MEK1/2, can be targeted with several highly specific inhibitors. The clinical activity of these inhibitors seems to be mixed, showing efficacy against mutant BRAF-driven tumors but not KRAS-driven tumors, such as pancreatic adenocarcinomas. To improve our understanding of this context- dependent efficacy, we generated pancreatic cancer cells resistant to MEK1/2 inhibition, which were also resistant to KRAS and ERK1/2 inhibitors. Compared with parental cells, inhibitor-resistant cells showed several phenotypic changes including increased metastatic ability in vivo. The transcription factor SLUG, which is known to induce epithelial-to-mesenchymal transition, was identified as the key factor responsible for both resistance to MEK1/2 inhibition and increased metastasis. Slug, but not similar transcription factors, predicted poor prognosis of pancreatic cancer patients and induced the transition to a cellular phenotype in which cell-cycle progression becomes independent of the KRASRAF-MEK1/2-ERK1/2 pathway. SLUG was targeted using two independent strategies: (i) inhibition of the MEK5-ERK5 pathway, which is responsible for upregulation of SLUG upon MEK1/2 inhibition, and (ii) direct PROTAC-mediated degradation. Both strategies were efficacious in preclinical pancreatic cancer models, paving the path for the development of more effective therapies against pancreatic cancer.Significance: This study demonstrates that SLUG confers resistance to MEK1/2 inhibitors in pancreatic cancer by uncoupling tumor progression from KRAS-RAF-MEK1/2-ERK1/2 signaling, providing new therapeutic opportunities.