1. Academic Validation
  2. Establishment of an acquired lorlatinib-resistant cell line of non-small cell lung cancer and its mediated resistance mechanism

Establishment of an acquired lorlatinib-resistant cell line of non-small cell lung cancer and its mediated resistance mechanism

  • Clin Transl Oncol. 2022 Nov;24(11):2231-2240. doi: 10.1007/s12094-022-02884-x.
Bo Xie  # 1 Ying Qiu  # 1 Juan Zhou 1 Dou Du 1 Haochuan Ma 1 Jiapeng Ji 1 Liquan Zhu 1 Weimin Zhang 2
Affiliations

Affiliations

  • 1 Department of Oncology, General Hospital of Southern Theater Command, PLA, No.111, Liuhua Rd., Guangzhou, 510010, China.
  • 2 Department of Oncology, General Hospital of Southern Theater Command, PLA, No.111, Liuhua Rd., Guangzhou, 510010, China. xiebodoctor@163.com.
  • # Contributed equally.
Abstract

Purpose: Although lorlatinib, the third generation of echinoderm microtubule protein 4-anaplastic lymphoma kinase (EML4-ALK) tyrosine kinase inhibitor (TKI), overcame the previous generation ALK-TKIs' drug resistance problems, but the mechanism of lorlatinib resistance remained unclear. Furthermore, optimal chemotherapy for lorlatinib-resistant non-small cell lung Cancer (NSCLC) patients was still unknown.

Methods: A lorlatinib-resistant NSCLC cell line SNU-2535LR was generated by gradually increasing dose of lorlatinib to crizotinib-resistant cell line SNU-2535 in vitro. To study the resistance mechanism of SNU-2535LR cells, we applied CCK-8 assay to detect the sensitivity of crizotinib and the reverse effect of APR-246, a p53 activator, on lorlatinib-induced resistance and different chemotherapy drugs to SNU-2535LR cells. We also detected the expressions of EML4-ALK-related proteins of SNU-2535LR cells via western blot.Please confirm that author names have been identified correctly and are presented in the right order.Dear Editor: I have carefully confirmed that the author names have been identified correctly and are presented in right order.Thank you very much! Your sincerely BoXie RESULTS: The sensitivity of SNU-2535LR cells to lorlatinib was decreased significantly than that of SNU-2535 cells. EML4-ALK fusion was decreased both at protein level and DNA level in SNU-2535LR cells. More interesting, the crizotinib-resistant mutation ALK p.G1269A disappeared, while new TP53 mutation emerged in SNU-2535LR cells. APR-246 can reverse the lorlatinib resistance in SNU-2535LR cells, with a reversal index of 4.768. Compared with SNU-2535 cells, the sensitivity of SNU-2535LR cells to gemcitabine, docetaxel and paclitaxel was significantly increased (P < 0.05), but decreased to cisplatin (P < 0.05).

Conclusion: This study demonstrated that the combination of p53 protein agonist and lorlatinib may provide a new therapeutic strategy for NSCLC patients with lorlatinib resistance and TP53 mutation. Furthermore, the results also provide guidance for selecting optimal chemo-regimens for NSCLC patients after ALK-TKIs failure.

Keywords

EML4-ALK; Lorlatinib resistance; Mechanism; Non-small cell lung cancer.

Figures
Products