JCI：抗精神病药TFP能够恢复耐药癌细胞的化学敏感性

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<div> 近日，来自美国纽约西奈山医学院的研究人员发现，靶向FOXO1/KLF6信号通路能够调节致癌的表皮生长因子受体信号，而且，抗精神病药物盐酸三氟拉嗪能够恢复抗EGFR药物耐受细胞的化学敏感性。相关研究成果于6月1日发表在<em>The Journal of Clinical Investigation</em>上。</div>
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表皮生长因子受体（EGFR）的激活是疾病发展的重要促进因素，到目前为止，靶向EGFR被广泛用于晚期癌症治疗药物的设计。然而，抗药性的发展极大的阻遏了癌症的治疗。进一步研究表明，这种抗药性主要通过几种机制而来，其中包括了AKT信号的激活。

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虽然已经知道很多特殊的分子病变导致了抗EGFR药物的耐药性的发展，但是，对EGFR信号的下游信号分子的研究，很可能会促进发现新的靶向分子来治疗这些耐药性疾病。

在体外培养的细胞及活体模型中，研究人员鉴定了一个与肿瘤抑制因子KLF6以及叉头转录因子FOXO1有关的转录信号网络，该网络能够负调控激活的EGFR信号。此外，在肺腺癌体外培养的细胞以及异种移植模型，他们研究了由美国食品和药物管理局(FDA）所批准的药物盐酸三氟拉嗪 (TFP，为抗精神病药及镇吐药)。结果发现，通过调节KLF6/FOXO1信号级联网络，该药物能够抑制FOXO1的出核转运，并恢复抗埃罗替尼（抗肿瘤药物）细胞的化学敏感性。

总的来说，该研究阐明了能够调节致癌EGFR信号的一种新的转录信号网络KLF6/FOXO1。而且还发现，在转移性肺腺癌的治疗过程中，盐酸三氟拉嗪能够恢复抗EGFR药物耐受癌细胞的化学敏感性。 
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<a title="" href="http://dx.doi.org/10.1172/JCI62058" target="_blank">doi: 10.1172/JCI62058</a>
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<br/><strong>Targeting the FOXO1/KLF6 axis regulates EGFR signaling and treatment response </strong><br/>


Jaya Sangodkar, Neil S. Dhawan, Heather Melville, Varan J. Singh, Eric Yuan, Huma Rana, Sudeh Izadmehr, Caroline Farrington, Sahar Mazhar, Suzanna Katz, Tara Albano, Pearlann Arnovitz, Rachel Okrent, Michael Ohlmeyer, Matthew Galsky, David Burstein, David Zhang, Katerina Politi, Analisa DiFeo and Goutham Narla.

EGFR activation is both a key molecular driver of disease progression and the target of a broad class of molecular agents designed to treat advanced cancer. Nevertheless, resistance develops through several mechanisms, including activation of AKT signaling.Though much is known about the specific molecular lesions conferring resistance to anti-EGFR–based therapies, additional molecular characterization of the downstream mediators of EGFR signaling may lead to the development of new classes of targeted molecular therapies to treat resistant disease.We identified a transcriptional network involving the tumor suppressors Krüppel-like factor 6 (KLF6) and forkhead box O1 (FOXO1) that negatively regulates activated EGFR signaling in both cell culture and in vivo models. Furthermore, the use of the FDA-approved drug trifluoperazine hydrochloride (TFP), which has been shown to inhibit FOXO1 nuclear export, restored sensitivity to AKT-driven erlotinib resistance through modulation of the KLF6/FOXO1 signaling cascade in both cell culture and xenograft models of lung adenocarcinoma.Combined, these findings define a novel transcriptional network regulating oncogenic EGFR signaling and identify a class of FDA-approved drugs as capable of restoring chemosensitivity to anti-EGFR–based therapy for the treatment of metastatic lung adenocarcinoma.

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  <br/>来源：生物谷

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