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

Oncogene volume 39, pages 1739–1755 (2020)Cite this article

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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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  1. These authors contributed equally: Jian Huang, Xiuwen Lan

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  1. The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150040, China

    Jian Huang, Ting Wang, Hailing Lu, Mengru Cao, Shi Yan, Yue Cui, Dexin Jia, Li Cai & Ying Xing

  2. Department of Critical Care Medicine, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150040, China

    Xiuwen Lan

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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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