Abstract
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) significantly prolong the survival time of non-small-cell lung cancer (NSCLC) patients with EGFR-activating mutations, but resistance develops universally. Activation of the phosphatidyl inositol-3 kinase (PI3K)/AKT signaling pathway and phenotypic alterations in epithelial–mesenchymal transition (EMT) are both mechanisms of acquired resistance to EGFR-TKIs. However, the mechanisms underlying this resistance remain unclear. In this study, EHD1 depletion significantly increased NSCLC cell sensitivity to EGFR-TKI, which was accompanied by EMT reversal. Microarray analysis showed that the PTEN/PI3K/AKT signaling pathway is a crucial pathway regulated by EHD1. Moreover, a PTEN inhibitor abolished EHD1 shRNA regulation of EGFR-TKI sensitivity, EMT, and cancer progression. Mass spectrometry showed that TUBB3 is a novel EHD1-interacting protein. EHD1 modulated microtubule stability by interacting with TUBB3. Furthermore, TUBB3 depletion significantly attenuated EHD1-induced EGFR-TKI resistance and EMT. Bioinformatics analysis revealed that EHD1 is significantly associated with the gene set, “Cellular Response to Interleukin-1β (IL-1β)”. As expected, treatment with IL-1β led to increased expression of EHD1, activation of PTEN/PI3K/AKT signaling, and induction of EMT in NSCLC cells. In patient specimens, EHD1 was highly expressed in EGFR-TKI-refractory specimens. EHD1 was positively associated with TUBB3 and IL-1R1 but negatively associated with PTEN. In addition, targeting the IL-1β/EHD1/TUBB3 axis mitigated cancer progression by inhibiting cell proliferation and metastasis and promoting apoptosis. Our study demonstrates the involvement of the IL-1β/EHD1/TUBB3 axis in EGFR-TKI resistance and provides a potential therapeutic approach for treating patients with NSCLC that has acquired EGFR-TKI resistance.
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Funding
This study was supported in part by grants from the Certificate of China Postdoctoral Science Foundation Grant (2015M581477, 2017M621307), the Hei Long Jiang Postdoctoral Foundation (LBH-Z15145, LBH-Z17182), the Natural Science and Technology Foundation of Heilongjiang Province (LC2016037), the Fundamental Research Funds for the Provincial Universities, the Hai Yan Youth Fund and Top-Notch Youth Fund from Harbin Medical University Cancer Hospital (JJQN2018-11, JJQN2018-02 and BJQN2019-07), and the NSFC (Grant Nos. 81772474, 81572276, 81803023 and 81602717).
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Huang, J., Lan, X., Wang, T. et al. Targeting the IL-1β/EHD1/TUBB3 axis overcomes resistance to EGFR-TKI in NSCLC. Oncogene 39, 1739–1755 (2020). https://doi.org/10.1038/s41388-019-1099-5
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DOI: https://doi.org/10.1038/s41388-019-1099-5
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