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Translational Therapeutics

Silencing of NUP62 overcomes osimertinib resistance via ubiquitination of survivin in non-small cell lung cancer cells

British Journal of Cancer (2026) Cite this article

Subjects

Abstract

Background

Osimertinib (OSI), a third-generation epidermal growth factor receptor tyrosine kinase inhibitor, is the standard first-line treatment for non-small cell lung cancer (NSCLC) patients harbouring epidermal growth factor receptor-activating mutations. Nevertheless, the emergence of acquired resistance to OSI in most patients limits long-term efficacy and yields only modest improvements in overall survival. We identified nucleoporin 62 (NUP62) knockdown as a potential strategy to overcome OSI resistance in NSCLC and investigated the underlying molecular mechanisms.

Methods

The role of NUP62 in OSI resistance was evaluated in parental and OSI-resistant NSCLC cell lines. mRNA expression of NUP62 was analysed in lung cancer patient cohorts, and survival rate of the patients was assessed using Kaplan Meier Plot. Mechanistic studies employed siRNA-mediated knockdown, CCK-8, clonogenic assays, immunohistochemistry, western blotting and flow cytometric assays in vitro. In vivo efficacy was examined in a xenograft mouse model.

Results

mRNA expression of NUP62 was significantly upregulated in lung cancer tissues and correlated with poor patient survival and increased recurrence. NUP62 knockdown using small interfering RNA (siRNA) sensitised OSI-resistant NSCLC cells to OSI, leading to reduced cell viability and impaired clonogenic potential. Combination of siRNA NUP62 and OSI induced apoptosis via activation of caspases, an effect abrogated by the pan-caspase inhibitor zVAD (carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone). Mechanistically, NUP62 knockdown markedly reduced survivin, a member of the inhibitor of apoptosis protein family. Survivin downregulation occurred through the ubiquitin-proteasome system, as shown by enhanced ubiquitination and a shortened protein half-life. Overexpressing survivin attenuated siRNA NUP62 plus OSI-induced cell death by inhibiting caspase-3 activity in OSI-resistant NSCLC cell lines. Furthermore, silencing of NUP62 significantly enhanced the antitumor activity of OSI and suppressed tumour growth in vivo.

Conclusion

NUP62 knockdown reverses OSI resistance by promoting ubiquitination of survivin in OSI-resistant NSCLC cell lines. Silencing of NUP62 may, therefore, be an effective strategy to overcome OSI resistance and enhance therapeutic efficacy.

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Fig. 1: NUP62 expression is upregulated in human lung cancer and is associated with patient survival probability.
The alternative text for this image may have been generated using AI.
Fig. 2: NUP62 knockdown sensitises OSI-resistant NSCLC cells by inducing apoptotic cell death.
The alternative text for this image may have been generated using AI.
Fig. 3: NUP62 depletion downregulates survivin expression.
The alternative text for this image may have been generated using AI.
Fig. 4: NUP62 knockdown reduces the survivin protein level via the ubiquitin–proteasome pathway.
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Fig. 5: NUP62 knockdown enhances OSI sensitivity in vivo.
The alternative text for this image may have been generated using AI.
Fig. 6: NUP62 knockdown overcomes OSI resistance in EGFR wild-type A549 cells.
The alternative text for this image may have been generated using AI.

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Acknowledgements

We thank Prof. K.S. Choi (Ajou University, Suwon, Republic of Korea) for helpful discussions and technical support.

Funding

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) (NRF-2020R1F1A1073962, RS-2024-00358981); by the Bio & Medical Technology Development Program of the NRF funded by the Korean government (MSIT) (RS-2023-00227084); by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (RS-2023-00261982), and by a grant (2024IP0086) from the Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea.

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  1. These authors contributed equally: Seok Soon Park, Hye Won Lee.

Authors and Affiliations

  1. Asan Institute for Life Sciences, ASAN Medical Center, Seoul, Republic of Korea

    Seok Soon Park, Hye Won Lee, Mi Ri Kwon, Eun Jin Ju, Seol Hwa Shin, Jin Park, Eun Jung Ko, Ga Won Son & Seong-Yun Jeong

  2. Asan Preclinical Evaluation Center for Cancer Therapeutix, ASAN Medical Center, Seoul, Republic of Korea

    Seok Soon Park, Mi Ri Kwon, Eun Jin Ju, Seol Hwa Shin, Jin Park, Eun Jung Ko, Tae Won Kim, Si Yeol Song & Seong-Yun Jeong

  3. Medical Research Institute, Kangbuk Samsung Hospital, Seoul, Republic of Korea

    Seok Soon Park

  4. Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea

    Hye Won Lee & Ga Won Son

  5. Department of Radiation Oncology, ASAN Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea

    Yeon Joo Kim & Si Yeol Song

  6. Department of Convergence Medicine, ASAN Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea

    Gyeong Joon Moon, Dong Ha Kim, Yun Jung Choi, Jin Kyung Rho & Seong-Yun Jeong

  7. Center for Cell Therapy, ASAN Medical Center, Seoul, Republic of Korea

    Gyeong Joon Moon

  8. Department of Life Science, Chung-Ang University, Seoul, Republic of Korea

    Yun-Yong Park

  9. Department of Oncology, ASAN Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea

    Tae Won Kim

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Contributions

SSP was responsible for conceptualisation, investigation, data analysis, funding acquisition and writing of the original draft and editing. HWL performed in vitro experiments and data analysis. EJJ and EJK conducted in vivo experiments. SHS and JP were responsible for result visualisation. GWS and MRK performed in vitro experiments. TWK contributed to funding acquisition. GJM and Y-YP carried out genomic data analysis. DHK, YJC and JKR provided cell lines. YJK and SYS offered clinical advice. S-YJ contributed to conceptualisation and funding acquisition.

Corresponding authors

Correspondence to Seok Soon Park, Si Yeol Song or Seong-Yun Jeong.

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All animal experiments were performed following a protocol approved by the Institutional Animal Care and Use Committee of the Asan Institute for Life Science (2024-40-038). Sample sizes of animal experiments were calculated using the ‘resource equation’: E = total number of animals − total number of groups, in which E should lie between 10 and 20. All patients provided signed informed consent. This study was approved by the Institutional Review Board (IRB) of Asan Medical Center (2014-0214).

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Park, S.S., Lee, H.W., Kwon, M.R. et al. Silencing of NUP62 overcomes osimertinib resistance via ubiquitination of survivin in non-small cell lung cancer cells. Br J Cancer (2026). https://doi.org/10.1038/s41416-026-03475-1

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