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

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

  • Oncogene. 2020 Feb;39(8):1739-1755. doi: 10.1038/s41388-019-1099-5.
Jian Huang  # 1 Xiuwen Lan  # 2 Ting Wang 1 Hailing Lu 1 Mengru Cao 1 Shi Yan 1 Yue Cui 1 Dexin Jia 1 Li Cai 3 Ying Xing 4
Affiliations

Affiliations

  • 1 The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150040, China.
  • 2 Department of Critical Care Medicine, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150040, China.
  • 3 The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150040, China. caili@ems.hrbmu.edu.cn.
  • 4 The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, 150 Haping Road, Harbin, 150040, China. xingying0618@163.com.
  • # Contributed equally.
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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