yuanhuadine and Carcinoma--Non-Small-Cell-Lung

Acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) has been a major obstacle in the treatment of non-small cell lung cancer (NSCLC) patients. AXL has been reported to mediate EGFR-TKIs. Recently, third generation EGFR-TKI osimertinib has been approved and yet its acquired resistance mechanism is not clearly understood. We found that AXL is involved in both gefitinib and osimertinib resistance using in vitro and in vivo model. In addition, AXL overexpression was correlated with extended protein degradation rate. We demonstrate targeting AXL degradation is an alternative route to restore EGFR-TKIs sensitivity. We confirmed that the combination effect of YD, an AXL degrader, and EGFR-TKIs can delay or overcome EGFR-TKIs-driven resistance in EGFR-mutant NSCLC cells, xenograft tumors, and patient-derived xenograft (PDX) models. Therefore, combination of EGFR-TKI and AXL degrader is a potentially effective treatment strategy for overcoming and delaying acquired resistance in NSCLC.

Topics: Acrylamides; Aniline Compounds; Animals; Antineoplastic Agents; Axl Receptor Tyrosine Kinase; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Drugs, Chinese Herbal; ErbB Receptors; Female; Gefitinib; Gene Expression Regulation, Neoplastic; Lung Neoplasms; Male; Mice, Nude; Protein Kinase Inhibitors; Proteolysis; Proto-Oncogene Proteins; Receptor Protein-Tyrosine Kinases; RNA, Small Interfering; Signal Transduction; Terpenes; Tumor Burden; Xenograft Model Antitumor Assays

The growth inhibition and antitumor activities of yuanhuadine (1), a daphnane diterpenoid from the flowers of Daphne genkwa, were investigated in human lung cancer cells. Compound 1 exhibited a relatively selective growth inhibition against human lung cancer cells compared to other solid human cancer cell lines. The potent antiproliferative activity by 1 was associated with cell-cycle arrest and modulation of cell-signaling pathways. Cell-cycle arrest in the G0/G1 and G2/M phase was induced by 1 in A549 human non-small-cell lung cancer cells, and these events were correlated with the expression of checkpoint proteins including the up-regulation of p21 and down-regulation of cyclins, cyclin-dependent kinases 2 (CDK2) and 4 (CDK4), and c-Myc. Compound 1 also suppressed the expression of the Akt/mammalian target of rapamycin (mTOR) and its downstream effector molecules including p70 S6 kinase (p70S6K) and eukaryotic initiation factor 4E-binding protein 1 (4EBP1). Ligand-induced epidermal growth factor receptor (EGFR) and c-Met signaling were also inhibited by 1. The oral administration of 1 (0.5 mg/kg body weight, daily) for 14 days significantly inhibited tumor growth in athymic xenograft nude mouse model bearing human lung A549 cells, without any overt toxicity. Synergistic antiproliferative effects of compound 1 were also found in combination with the EGFR inhibitor gefitinib. Cell-cycle arrest and suppression of Akt/mTOR and EGFR signaling pathways might be plausible mechanisms of actions for the antiproliferative and antitumor activity of 1 in human non-small-cell lung cancer cells.

Topics: Animals; Antineoplastic Agents, Phytogenic; Carcinoma, Non-Small-Cell Lung; Cell Cycle; Daphne; Disease Models, Animal; Diterpenes; Down-Regulation; ErbB Receptors; Female; Flowers; Humans; Mice; Mice, Nude; Molecular Structure; Terpenes