Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, USA.
J Clin Invest. 2012 Jul;122(7):2637-51. doi: 10.1172/JCI62058. Epub 2012 Jun 1.
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.
表皮生长因子受体（EGFR）的激活不仅是疾病进展的关键分子驱动因素，也是一类旨在治疗晚期癌症的广泛分子药物的靶点。然而，通过多种机制会产生耐药性，包括 AKT 信号的激活。尽管人们对赋予抗 EGFR 治疗耐药性的特定分子病变有了很多了解，但对 EGFR 信号下游介质的进一步分子表征可能会导致开发新的靶向分子治疗方法来治疗耐药性疾病。我们确定了一个涉及肿瘤抑制因子 Krüppel 样因子 6（KLF6）和叉头框 O1（FOXO1）的转录网络，该网络负调节细胞培养和体内模型中激活的 EGFR 信号。此外，使用已被证明可抑制 FOXO1 核输出的 FDA 批准药物三氟拉嗪盐酸盐（TFP），通过调节细胞培养和肺腺癌异种移植模型中的 KLF6/FOXO1 信号级联，恢复了对 AKT 驱动的厄洛替尼耐药的敏感性。综上所述，这些发现定义了一个调节致癌性 EGFR 信号的新转录网络，并确定了一类 FDA 批准的药物能够恢复对基于抗 EGFR 的治疗转移性肺腺癌的化疗敏感性。
