Anti-EGFR therapy can overcome acquired resistance to the third-generation ALK-tyrosine kinase inhibitor lorlatinib mediated by activation of EGFR.

in Acta pharmacologica Sinica by Chen Hu, Cong-Hua Lu, Jie Zheng, Jun Kang, Dai-Juan Huang, Chao He, Yi-Hui Liu, Zhan-Rui Liu, Di Wu, Yuan-Yao Dou, Yi-Min Zhang, Cai-Yu Lin, Rui Han, Yong He

TLDR

  • A study investigated the mechanisms of acquired resistance to the ALK-TKI lorlatinib and identified EGFR activation as a key driver of resistance.
  • Combination treatment with ALK-TKI and anti-EGFR agents was found to be effective in suppressing acquired resistance to ALK-TKIs.
  • The study suggests that anti-EGFR treatment may be a promising approach for treating resistance to ALK-TKIs in patients with ALK-positive NSCLC.

Abstract

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related mortality. Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are standard treatments for EML4-ALK-positive NSCLC, but resistance to these agents remains a challenge. This study aimed to determine the mechanisms of acquired resistance to the third-generation ALK-TKI lorlatinib. Lorlatinib-resistant cell lines were established by prolonged exposure to a high concentration of lorlatinib. Activation of epidermal growth factor receptor (EGFR) caused by a decrease in endocytosis and degradation of protein was demonstrated to play an essential role in acquired resistance to lorlatinib. The interaction between the EGFR and ALK was investigated to identify binding sites and conformational changes in ALK. We performed high-throughput compound screening using a small-molecule drugs library comprising 510 antitumor agents in an effort to discover small-molecule compounds that target EGFR in lorlatinib-resistant cells. Combination treatment with ALK-TKI and anti-EGFR agents suppressed acquired resistance to ALK-TKIs caused by activation of EGFR in vitro and in vivo, suggesting that the combination of lorlatinib and an anti-EGFR agent could be effective in patients with lorlatinib-resistant NSCLC. This research provides insights into the mechanism of resistance to lorlatinib and suggests that it can be overcome by anti-EGFR treatment, offering a promising approach for treating resistance to lorlatinib mediated by EGFR activation in patients with ALK-positive NSCLC.

Overview

  • The study aims to determine the mechanisms of acquired resistance to the third-generation ALK-TKI lorlatinib.
  • Lorlatinib-resistant cell lines were established by prolonged exposure to a high concentration of lorlatinib.
  • The study investigates the interaction between EGFR and ALK and identifies binding sites and conformational changes in ALK.

Comparative Analysis & Findings

  • Activation of EGFR through decreased endocytosis and degradation of protein was found to play an essential role in acquired resistance to lorlatinib.
  • High-throughput compound screening identified small-molecule compounds that target EGFR in lorlatinib-resistant cells.
  • Combination treatment with ALK-TKI and anti-EGFR agents suppressed acquired resistance to ALK-TKIs caused by EGFR activation in vitro and in vivo.

Implications and Future Directions

  • The study provides insights into the mechanism of resistance to lorlatinib and suggests that it can be overcome by anti-EGFR treatment.
  • The combination of lorlatinib and an anti-EGFR agent could be effective in patients with lorlatinib-resistant NSCLC.
  • Future studies could explore the possibility of using anti-EGFR treatment as a complementary therapy to overcome resistance to ALK-TKIs.
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