Targeting the IL-1β/EHD1/TUBB3 axis overcomes resistance to EGFR-TKI in NSCLC

Huang, Jian; Lan, Xiuwen; Wang, Ting; Lu, Hui; Cao, Ming; Shi, Yan; Cui, Yue; Jia, Dexin; Cai, Li; Xing, Ying

doi:10.1038/s41388-019-1099-5

Cited by 40 publications

(50 citation statements)

References 68 publications

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“…Next, we sought to explore the potential mechanism by which 14-3-3ζ knockdown regulates EGFR-TKI resistance. EMT is involved in phenotypic changes, which were identified as one of the EGFR-TKI resistance mechanisms ( 7 , 9 ). The 14-3-3ζ depletion in EGFR-TKI-resistant cells led to the upregulation of epithelial markers (E-cadherin) and the downregulation of mesenchymal markers (N-cadherin and vimentin) ( Figure 4A ).…”

Section: Resultsmentioning

confidence: 99%

“…Human NSCLC cell lines H1975 (EGFR L858R/T790M mutations; gefitinib resistant), PC9 (EGFR with deletion of E746_A750; gefitinib sensitive), and PC9/GR (gefitinib-resistant PC9 cell line) were maintained in our laboratory, as previously reported ( 9 , 33 ).…”

Section: Methodsmentioning

confidence: 99%

“…Cells at a density of 1 × 10 6 cells/well were seeded in six-well plates. When the cells were grown to 80 to 90% confluence, a cross-shaped wound was scratched by dragging a 10-μl sterile pipette tip across the monolayers of cells, and the cell debris were rinsed with phosphate-buffered saline (PBS) ( 9 ). The process of wound healing was then observed at 0, 24, and 48 h, and the cells were stained with crystal violet at 48 h for a clearer view of the wound.…”

Section: Methodsmentioning

confidence: 99%

“…Microarray processing and analysis were performed as previously described ( 9 ). To define the gene expression profiles, Affymetrix Human GeneChip PrimeView (Thermo Fisher Science, Catalog number: 902487) was used for microarray analysis according to the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

“…The identified acquired resistance mechanisms have been mainly categorized as secondary mutations in the EGFR gene (T790M and other rare mutations), the activation of alternative signaling pathways, and phenotypic changes such as epithelial–mesenchymal transition (EMT) ( 7 , 8 ). The unpredictability and diversity of EGFR-TKI resistance mechanisms present a challenge for developing innovative treatment strategies that can overcome EGFR-TKI resistance in patients ( 9 ).…”

Section: Introductionmentioning

confidence: 99%

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Targeting 14-3-3ζ Overcomes Resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors in Lung Adenocarcinoma via BMP2/Smad/ID1 Signaling

et al. 2020

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Background: The 14-3-3ζ protein, which acts as a putative oncoprotein, has been found to promote the proliferation, metastasis, and chemoresistance of cancer cells in several cancers including lung adenocarcinoma (LUAD); however, its significance in epidermal growth factor receptor–tyrosine kinase inhibitor (EGFR-TKI) resistance remains unknown. Methods: The Cancer Genome Atlas (TCGA) database was used to determine 14-3-3ζ expression in pancancer and LUAD. 14-3-3ζ and ID1 expression was then examined in clinical LUAD samples by immunohistochemistry (IHC). Lentiviral transfection with 14-3-3ζ-specific small hairpin RNA (shRNA) was used to establish stable 14-3-3ζ knockdown gefitinib-resistant PC9 (PC9/GR) and H1975 cell lines. The effect of 14-3-3ζ knockdown on reversing EGFR-TKI resistance was determined in vitro by Cell Counting Kit-8 (CCK-8), wound healing, Transwell assays, and flow cytometry. A xenograft tumor model was established to evaluate the role of 14-3-3ζ in EGFR-TKI resistance. Microarray analysis results showed multiple pathways regulated by 14-3-3ζ-shRNA. Results: In the present study, we demonstrated that based on the TCGA, pancancer and LUAD 14-3-3ζ expression was elevated and predicted unfavorable prognosis. In addition, high 14-3-3ζ expression was associated with advanced T stage, TNM stage, presence of lymph node metastasis and, importantly, poor treatment response to EGFR-TKIs in LUAD patients with EGFR-activating mutations. 14-3-3ζ shRNA sensitized EGFR-TKI-resistant human LUAD cells to gefitinib and reversed epithelial-to-mesenchymal transition (EMT). After 14-3-3ζ depletion, bone morphogenetic protein (BMP) signaling activation was decreased in EGFR-TKI-resistant cells in microarray analysis, which was further validated by Western blot analysis. Furthermore, the expression of 14-3-3ζ positively correlates with ID1 expression in human EGFR-mutant LUAD patient samples. In vivo , there was a reduction in the tumor burden in mice treated with 14-3-3ζ shRNA and gefitinib compared to mice treated with gefitinib alone. Conclusion: Our work uncovers a hitherto unappreciated role of 14-3-3ζ in EGFR-TKI resistance. This study might provide a potential therapeutic approach for treating LUAD patients harboring EGFR mutations.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Targeting 14-3-3ζ Overcomes Resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors in Lung Adenocarcinoma via BMP2/Smad/ID1 Signaling

et al. 2020

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Targeting TUBB3 Suppresses Anoikis Resistance and Bone Metastasis in Prostate Cancer

Dong,

Gu,

Sun

et al. 2024

Adv Healthcare Materials

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Bone metastases occur in more than 70% of advanced prostate cancer (PCa) patients, leading to a poor prognosis. Resistance to detachment‐induced apoptosis, also known as anoikis, plays a crucial role in the onset of tumor metastasis. Targeting anoikis resistance is of immense therapeutic significance in repression of metastatic spread. In this study, based on an anoikis‐related prognostic risk model of PCa, we identify TUBB3 as a key anoikis‐related prognostic gene that is highly expressed in bone metastatic PCa. TUBB3 expression is increased in anoikis‐resistant PCa cells, and TUBB3 depletion significantly reverses anoikis resistance during extracellular matrix (ECM) detachment and inhibits anoikis‐resistance‐induced PCa cell invasion and migration as well as epithelial‐mesenchymal transition (EMT) process. TUBB3 knockdown significantly reduces αvβ3/FAK/Src axis activation, blocking its downstream oncogenic signaling. In addition, we develop bone‐targeting lipid nanoparticles (BT‐LNP) based on bisphosphonate‐modified ionizable lipid for systemic delivery of siRNA targeting TUBB3 (siTUBB3). BT‐LNP‐delivered siTUBB3 therapy with localization in the bone microenvironment significantly attenuate PCa bone metastasis progression in vivo upon intravenous administration. These findings pinpoint that TUBB3, as a key regulator of anoikis resistance, is an effective therapeutic target in bone metastatic PCa and that BT‐LNP‐mediated systemic delivery of siTUBB3 can be developed as a novel therapeutic strategy for this disease.This article is protected by copyright. All rights reserved

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Exosomal TUBB3 mRNA expression of metastatic castration‐resistant prostate cancer patients: Association with patient outcome under abiraterone

Zhu

Sun

et al. 2021

Cancer Medicine

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Targeting the IL-1β/EHD1/TUBB3 axis overcomes resistance to EGFR-TKI in NSCLC

Cited by 40 publications

References 68 publications

Targeting 14-3-3ζ Overcomes Resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors in Lung Adenocarcinoma via BMP2/Smad/ID1 Signaling

Targeting 14-3-3ζ Overcomes Resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors in Lung Adenocarcinoma via BMP2/Smad/ID1 Signaling

Targeting TUBB3 Suppresses Anoikis Resistance and Bone Metastasis in Prostate Cancer

Exosomal TUBB3 mRNA expression of metastatic castration‐resistant prostate cancer patients: Association with patient outcome under abiraterone

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