眾所周知過度活躍的表皮生長因子受體（EGFR）信號與癌癥的發(fā)生發(fā)展有密切聯(lián)系。目前,，已經(jīng)開發(fā)了一些治療與表皮生長因子受體相關(guān)的癌癥藥物,，然而許多患者已經(jīng)出現(xiàn)了這些藥物的耐受，因此這些藥物治療并不能取預(yù)期效果,。
近日，一項(xiàng)最近的臨床研究希望能進(jìn)一步了解表皮生長因子受體在癌癥中的作用,，以便設(shè)計(jì)出更好的靶向表皮生長因子受體信號通路的藥物,，相關(guān)研究論文發(fā)表在Journal of Clinical Investigation雜志上。
使用人癌細(xì)胞肺組織和表皮生長因子受體相關(guān)的肺癌小鼠模型,，研究小組發(fā)現(xiàn)兩個(gè)抑癌基因KLF6和FOXO1,，能破壞過度活躍的EGFR信號。
研究人員發(fā)現(xiàn)FDA批準(zhǔn)的藥物三氟拉嗪鹽酸（TFP）,，能增加FoxO1基因的活性,，恢復(fù)抗EGFR的藥物厄洛替尼的抗腫瘤功效,，抑制了腫瘤的生長。（生物谷：Bioon.com）
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. Singh1, 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.
