近日,，來自美國(guó)紐約西奈山醫(yī)學(xué)院的研究人員發(fā)現(xiàn),，靶向FOXO1/KLF6信號(hào)通路能夠調(diào)節(jié)致癌的表皮生長(zhǎng)因子受體信號(hào),，而且,，抗精神病藥物鹽酸三氟拉嗪能夠恢復(fù)抗EGFR藥物耐受細(xì)胞的化學(xué)敏感性。相關(guān)研究成果于6月1日發(fā)表在The Journal of Clinical Investigation上,。
表皮生長(zhǎng)因子受體（EGFR）的激活是疾病發(fā)展的重要促進(jìn)因素,，到目前為止，靶向EGFR被廣泛用于晚期癌癥治療藥物的設(shè)計(jì),。然而,，抗藥性的發(fā)展極大的阻遏了癌癥的治療,。進(jìn)一步研究表明，這種抗藥性主要通過幾種機(jī)制而來,，其中包括了AKT信號(hào)的激活,。
雖然已經(jīng)知道很多特殊的分子病變導(dǎo)致了抗EGFR藥物的耐藥性的發(fā)展，但是,，對(duì)EGFR信號(hào)的下游信號(hào)分子的研究,，很可能會(huì)促進(jìn)發(fā)現(xiàn)新的靶向分子來治療這些耐藥性疾病。
在體外培養(yǎng)的細(xì)胞及活體模型中,，研究人員鑒定了一個(gè)與腫瘤抑制因子KLF6以及叉頭轉(zhuǎn)錄因子FOXO1有關(guān)的轉(zhuǎn)錄信號(hào)網(wǎng)絡(luò),，該網(wǎng)絡(luò)能夠負(fù)調(diào)控激活的EGFR信號(hào),。此外,，在肺腺癌體外培養(yǎng)的細(xì)胞以及異種移植模型，他們研究了由美國(guó)食品和藥物管理局(FDA）所批準(zhǔn)的藥物鹽酸三氟拉嗪 (TFP,，為抗精神病藥及鎮(zhèn)吐藥),。結(jié)果發(fā)現(xiàn)，通過調(diào)節(jié)KLF6/FOXO1信號(hào)級(jí)聯(lián)網(wǎng)絡(luò),，該藥物能夠抑制FOXO1的出核轉(zhuǎn)運(yùn),，并恢復(fù)抗埃羅替尼（抗腫瘤藥物）細(xì)胞的化學(xué)敏感性。
總的來說,，該研究闡明了能夠調(diào)節(jié)致癌EGFR信號(hào)的一種新的轉(zhuǎn)錄信號(hào)網(wǎng)絡(luò)KLF6/FOXO1,。而且還發(fā)現(xiàn)，在轉(zhuǎn)移性肺腺癌的治療過程中,，鹽酸三氟拉嗪能夠恢復(fù)抗EGFR藥物耐受癌細(xì)胞的化學(xué)敏感性,。（生物谷Deepblue編譯）
doi: 10.1172/JCI62058
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Targeting the FOXO1/KLF6 axis regulates EGFR signaling and treatment response
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.
