The Secretome Engages STAT3 to Favor a Cytokine-rich Microenvironment in Mediating Acquired Resistance to FGFR Inhibitors
The Secretome Engages STAT3 to Favor a Cytokine-rich Microenvironment in Mediating Acquired Resistance to FGFR Inhibitors
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DOI：
10.1158/1535-7163.mct-18-0179
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发表时间：
2018-12
影响因子：
5.7
通讯作者：
Xinyi Wang;Jing Ai;Hongyan Liu;Xia Peng;Hui Chen;Yi Chen;Yi Su;Ai-jun Shen;Xun Huang;Jian Ding;M. Geng
中科院分区：
文献类型：
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作者：
Xinyi Wang;Jing Ai;Hongyan Liu;Xia Peng;Hui Chen;Yi Chen;Yi Su;Ai-jun Shen;Xun Huang;Jian Ding;M. Geng
获得性耐药严重阻碍了小分子抑制剂的应用。我们对与FGFR相关的获得性耐药性的理解是有限的。在这里，为了探索FGFR异常癌细胞中获得性耐药的潜在机制，我们产生了对多种FGFR抑制剂（FGFRi）具有耐药性的细胞，并研究了获得性耐药的潜在机制。我们发现分泌组的重编程与对FGFR1的获得性抗性密切相关。分泌组通过其同源受体激活转录因子STAT3来驱动获得性抗性。此外，巨噬细胞和成纤维细胞可以与癌细胞相互作用，通过促进过度和动态的细胞因子分泌以及STAT3激活来增强获得性抗性。我们还发现，Hsp90和HDAC抑制剂可以基本上同时抑制耐药细胞的增殖，多种细胞因子的分泌和STAT3的激活。我们的研究提供了关于在临床试验中用FGFRi治疗后在巨噬细胞和成纤维细胞丰富的肺癌和乳腺肿瘤患者中观察到的疗效差的转化见解。
Acquired resistance severely hinders the application of small-molecule inhibitors. Our understanding of acquired resistance related to FGFRs is limited. Here, to explore the underlying mechanism of acquired resistance in FGFR-aberrant cancer cells, we generated cells resistant to multiple FGFR inhibitors (FGFRi) and investigated the potential mechanisms underlying acquired resistance. We discovered that reprogramming of the secretome is closely associated with acquired resistance to FGFRi. The secretome drives acquired resistance by activating the transcription factor STAT3 via its cognate receptors. Moreover, macrophages and fibroblasts could interact with cancer cells to enhance acquired resistance by promoting exaggerated and dynamic cytokine secretion, as well as STAT3 activation. We also found that Hsp90 and HDAC inhibitors could substantially and simultaneously suppress the proliferation of resistant cells, the secretion of multiple cytokines, and the activation of STAT3. Our study offers translational insights concerning the poor efficacy observed in patients with macrophage- and fibroblast-rich lung cancers and breast tumors after treatment with FGFRi in clinical trials.