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Background <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusion <p>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.</p>

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

  • 期刊论文

  • 发表日期：

    2026年5月26日

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  • Seok Soon Park,
  • Hye Won Lee,
  • Mi Ri Kwon,
  • Eun Jin Ju,
  • Seol Hwa Shin,
  • Jin Park,
  • Eun Jung Ko,
  • Ga Won Son,
  • Yeon Joo Kim,
  • Gyeong Joon Moon,
  • Dong Ha Kim,
  • Yun Jung Choi,
  • Jin Kyung Rho,
  • Yun-Yong Park,
  • Tae Won Kim,
  • Si Yeol Song,
  • Seong-Yun Jeong

摘要

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.