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DUSP1 Promotes Osimertinib Drug-Tolerant Persistence by Inhibiting MAPK/ERK Signaling in Non-small Cell Lung Cancer

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Abstract

EGFR tyrosine kinase inhibitors (EGFR-TKIs) are the first-line treatment for EGFR-mutant non-small cell lung cancer (NSCLC) patients, which remarkably improve the clinical outcomes. However, drug resistance has greatly impaired the efficacy of EGFR-TKIs and contributes to cancer treatment failure. DUSP1, a negative regulator of MAPK signaling pathway, was discovered to mediate drug resistance in multiple types of cancers. Our study aimed to explore the role of DUSP1 in NSCLC cell resistance to osimertinib, a third-generation EGFR-TKI. Human NSCLC cell lines PC-9 and HCC827 were exposed to increasing concentrations of osimertinib for over 6 months to generate osimertinib resistant cells (PC-9-OR and HCC827-OR). The viabilities of osimertinib-resistant and parental sensitive NSCLC cells in response to osimertinib stimulation were detected by MTS assay and the IC50 values for osimertinib were obtained. The differentially expressed genes in osimertinib-resistant and sensitive NSCLC cells were identified by analyzing the GEO dataset GSE106765 using bioinformatic tools. DUSP1 expression was knocked down by using the short hairpin RNAs (shRNAs). Then, the effects of DUSP1 silencing on osimertinib-resistant and sensitive NSCLC cell resistance to osimertinib, viability, proliferation and apoptosis were assessed through loss-of-function experiments. The expression of key molecules (JNK, ERK, and p38 MAPK) in the MAPK signaling pathway was detected through western blotting analysis. DUSP1 was overexpressed in osimertinib-resistant NSCLC cells versus parental sensitive cells. DUSP1 silencing attenuated the resistance of NSCLC cells to osimertinib. DUSP1 silencing markedly inhibited osimertinib-resistant and sensitive NSCLC cell proliferation but enhanced cell apoptosis. Mechanically, DUSP1 knockdown increased phosphorylated-JNK, ERK, and p38 MAPK levels in NSCLC cells. Treatment with SB203580, the p38 MAPK inhibitor, reversed the effects of DUSP1 silencing on osimertinib-resistant NSCLC cell resistance to osimertinib, cell proliferation and apoptosis. DUSP1 downregulation restores the sensitivity of NSCLC cells to osimertinib via activating the MAPK signaling pathway.

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Data Availability

The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This work was supported by Hubei Provincial Natural Science Foundation of China (2022CFB951) and the Medical Research Fund of Wuhan Municipal Health Commission (WX21Q14).

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Authors and Affiliations

  1. Department of Pharmacy, Wuhan Fourth Hospital, Wuhan, 430030, China

    Wenjuan He, Ping Liu, Quan Lei, Jun Xu & Li Liu

  2. Wuhan Fourth Hospital, No.473, Hanzheng Street, Qiaokou District, Wuhan, Hubei Province, China

    Li Liu

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  1. Wenjuan He
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  2. Ping Liu
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  3. Quan Lei
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  4. Jun Xu
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  5. Li Liu
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Contributions

WH were the main designers of this study. WH, PL, QL, JX and LL performed the experiments and analyzed the data. WH and LL drafted the manuscript. All authors read and approved the final manuscript.

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Correspondence to Li Liu.

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Our study did not require an ethical board approval because it did not contain human or animal trials.

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He, W., Liu, P., Lei, Q. et al. DUSP1 Promotes Osimertinib Drug-Tolerant Persistence by Inhibiting MAPK/ERK Signaling in Non-small Cell Lung Cancer. Mol Biotechnol (2024). https://doi.org/10.1007/s12033-024-01127-4

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