Concurrent use of anlotinib overcomes acquired resistance to EGFR‐TKI in patients with advanced EGFR‐mutant non‐small cell lung cancer

• Published in: Thoracic cancer Vol. 12; no. 19; pp. 2574 - 2584
• Main Authors: Zhang, Chen, Cao, Honggang, Cui, Yanan, Jin, Shidai, Gao, Wen, Huang, Chenjun, Guo, Renhua
• Format: Journal Article
• Language: English
• Published: Melbourne John Wiley & Sons Australia, Ltd 01.10.2021; John Wiley & Sons, Inc; Wiley
• Subjects: acquired resistance; Adult; Aged; Aged, 80 and over; Animals; anlotinib; Apoptosis; Apoptosis - drug effects; Cancer therapies; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Cell growth; Cell Line, Tumor; Disease Models, Animal; Down-Regulation; Drug Resistance, Neoplasm - drug effects; Drug Therapy, Combination; EGFR‐TKI; ErbB Receptors - genetics; Experiments; Female; Gefitinib - pharmacology; Humans; Indoles - pharmacology; Kinases; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Male; Mice; Mice, Inbred BALB C; Middle Aged; non‐small cell lung cancer; Original; Protein Kinase Inhibitors - pharmacology; Proteins; Quinolines - pharmacology; Retrospective Studies; Vascular endothelial growth factor; VEGFR; non-small cell lung cancer; VEGFR; EGFR-TKI; anlotinib; acquired resistance
• ISSN: 1759-7706; 1759-7714
• DOI: 10.1111/1759-7714.14141

Background Acquired resistance development is a major challenge in the epidermal growth factor receptor‐tyrosine kinase inhibitor (EGFR–TKI) treatment of non–small cell lung cancer (NSCLC). Here, we investigated the potential effects of the concurrent use of anlotinib and EGFR‐TKI to overcome acquired resistance. Methods We conducted a preclinical study to evaluate the antitumor effects of gefitinib + anlotinib in gefitinib‐resistant lung adenocarcinoma models in vitro and in vivo. We then investigated the treatment effect of EGFR–TKI + anlotinib therapy in 24 advanced EGFR‐mutant NSCLC patients after EGFR‐TKI acquired resistance between January 2018 and August 2020. Results Anlotinib reversed gefitinib resistance in gefitinib‐resistant lung adenocarcinoma models by enhancing the antiproliferative and proapoptotic effects of gefitinib. The gefitinib + anlotinib treatment exerted a synergistic antitumor effect by downregulating the activation of VEGFR2 and downstream effectors, Akt and ERK. The EGFR–TKI + anlotinib therapy exhibited an objective response rate of 20.8% and a disease control rate of 95.8%. Median progression‐free survival (PFS) was 11.53 ± 2.41 months, but median overall survival was not reached. The median PFS was longer in patients experiencing gradual progression (13.30 ± 1.69 months) than in patients with dramatic progression (6.80 ± 1.75 months, p = 0.017). One grade 3 adverse event was noted (diarrhea, n = 2, 8.3%), and grade 4 or 5 adverse events were absent. Conclusions EGFR–TKI combined with anlotinib demonstrated powerful antitumor activity in vitro and in vivo. Concurrent use of anlotinib overcomes acquired resistance to EGFR‐TKI in advanced EGFR‐mutant NSCLC patients. Gefitinib and anlotinib synergistically promoted PC9/GR cells proliferation and inhibited PC9/GR cells apoptosis through the inhibition of EGFR phosphorylation, VEGFR2 phosphorylation and the downregulation of ERK and Akt signaling.