PDF(Pubmed)
Abstract：
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, which lacks effective therapies. Here, we demonstrate that the transcription factor, homeobox C6 (HOXC6), is overexpressed in most PDACs, and its inhibition blocks PDAC tumor growth and metastasis. HOXC6 transcriptionally activates tumor-promoting kinase MSK1 and suppresses tumor-inhibitory protein PPP2R2B in PDAC. HOXC6-induced PPP2R2B suppression causes mammalian target of rapamycin (mTOR) pathway activation, which facilitates PDAC growth. Also, MSK1 upregulation by HOXC6 is necessary for PDAC growth because of its ability to suppress apoptosis via its substrate DDX17. Combinatorial pharmacological inhibition of MSK1 and mTOR potently suppressed PDAC tumor growth and metastasis in PDAC mouse models. PDAC cells with acquired resistance to MSK1/mTOR-inhibitors displayed activated insulin-like growth factor 1 receptor (IGF1R) signaling and were successfully eradicated by IGF1R inhibitor. Furthermore, MEK inhibitor trametinib enhanced the efficacy of dual MSK1 and mTOR inhibition. Collectively, these results identify therapeutic vulnerabilities of PDAC and an approach to overcome acquired drug resistance to prolong therapeutic benefit.
摘要：
胰腺导管腺癌（PDAC）是最致命的癌症之一，缺乏有效的治疗方法。这里,我们证明了转录因子，homeoboxC6(HOXC6),在大多数PDAC中过表达，并且其抑制阻断PDAC肿瘤的生长和转移。HOXC6转录激活肿瘤促进激酶MSK1并抑制PDAC中的肿瘤抑制蛋白PPP2R2B。HOXC6诱导的PPP2R2B抑制导致哺乳动物雷帕霉素靶蛋白（mTOR）通路激活，这促进了PDAC的增长。此外，HOXC6对MSK1的上调是PDAC生长所必需的，因为它具有通过其底物DDX17抑制凋亡的能力。MSK1和mTOR的组合药理学抑制在PDAC小鼠模型中有效抑制PDAC肿瘤生长和转移。对MSK1/mTOR抑制剂具有获得性抗性的PDAC细胞显示出激活的胰岛素样生长因子1受体（IGF1R）信号，并被IGF1R抑制剂成功根除。此外，MEK抑制剂曲美替尼增强了双重MSK1和mTOR抑制的功效。总的来说，这些结果确定了PDAC的治疗脆弱性和克服获得性耐药以延长治疗获益的方法.
