TFF3 drives Hippo dependent EGFR-TKI resistance in lung adenocarcinoma.

IF 6.9 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Oncogene Pub Date : 2024-12-10 DOI:10.1038/s41388-024-03244-5
Shuwei Zhang, Yan Qin Tan, Xi Zhang, Basappa Basappa, Tao Zhu, Vijay Pandey, Peter E Lobie
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Abstract

Intrinsic and acquired resistance represent major obstacles to optimize outcomes in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) targeted therapy in lung adenocarcinoma (LUAD). Hence, a deeper understanding of EGFR-TKI resistance mechanisms in LUAD will potentially assist in formulating strategies to delay or overcome such resistance. Herein, it was observed that trefoil factor 3 (TFF3) is a crucial mediator of the LUAD EGFR-TKI response. TFF3 conferred intrinsic resistance to EGFR inhibition in LUAD by promotion of EGFR activation. TFF3 expression was also increased in acquired EGFR-TKI resistant LUAD, accompanied by reduced EGFR activation. YAP, a key mediator of the Hippo signaling, was positively regulated by TFF3 by post-transcriptional mechanisms and was responsible for acquired EGFR-TKI resistance mediated by TFF3. Inhibition of TFF3 by a small molecule inhibitor not only enhanced EGFR-TKI sensitivity in LUAD cells but also restored the sensitivity of acquired EGFR-TKI resistant LUAD cells to EGFR-TKIs in vitro and in vivo. These findings demonstrate a pivotal function of TFF3 in mediating both intrinsic and acquired EGFR-TKI resistance in LUAD and may offer a potential therapeutic mechanism for delaying or overcoming resistance to EGFR-TKIs.

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TFF3驱动肺腺癌中Hippo依赖性EGFR-TKI耐药。
内在和获得性耐药是优化表皮生长因子受体(EGFR)酪氨酸激酶抑制剂(TKI)靶向治疗肺腺癌(LUAD)疗效的主要障碍。因此,对LUAD中EGFR-TKI耐药机制的深入了解将有助于制定延迟或克服这种耐药的策略。本文观察到三叶因子3 (TFF3)是LUAD EGFR-TKI反应的重要介质。TFF3通过促进EGFR激活,赋予LUAD对EGFR抑制的内在抗性。在获得性EGFR- tki抗性LUAD中,TFF3表达也增加,并伴有EGFR激活降低。YAP是Hippo信号通路的关键介质,通过转录后机制受到TFF3的正调控,并参与了TFF3介导的获得性EGFR-TKI耐药。小分子抑制剂抑制TFF3不仅增强了LUAD细胞对EGFR-TKI的敏感性,而且在体外和体内恢复了获得性EGFR-TKI抗性LUAD细胞对EGFR-TKI的敏感性。这些发现证明了TFF3在LUAD中介导内源性和获得性EGFR-TKI抗性的关键功能,并可能提供延缓或克服对EGFR-TKI抗性的潜在治疗机制。
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来源期刊
Oncogene
Oncogene 医学-生化与分子生物学
CiteScore
15.30
自引率
1.20%
发文量
404
审稿时长
1 months
期刊介绍: Oncogene is dedicated to advancing our understanding of cancer processes through the publication of exceptional research. The journal seeks to disseminate work that challenges conventional theories and contributes to establishing new paradigms in the etio-pathogenesis, diagnosis, treatment, or prevention of cancers. Emphasis is placed on research shedding light on processes driving metastatic spread and providing crucial insights into cancer biology beyond existing knowledge. Areas covered include the cellular and molecular biology of cancer, resistance to cancer therapies, and the development of improved approaches to enhance survival. Oncogene spans the spectrum of cancer biology, from fundamental and theoretical work to translational, applied, and clinical research, including early and late Phase clinical trials, particularly those with biologic and translational endpoints.
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