Mediating EGFR-TKI Resistance by VEGF/VEGFR Autocrine Pathway in Non-Small Cell Lung Cancer

Cells

Thomas J. Smith¹  Chike Osude²  Meet Patel²  Aayush Rastogi²  Adijan Kuckovic²  Leo Lin²  Joseph Berei²  Namrata Dube²  Neelu Puri²  Adam Eckburg²  Shruti Gautam²  Shylendra B. Sreenivassappa³ 

[1] College of Education, Northern Illinois University, Dekalb, IL 60115, USA;Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, IL 61107, USA;Department of Hematology/Oncology, OSF Saint Anthony Medical Center, Rockford, IL 61107, USA;

关键词: non-small cell lung cancer (NSCLC);    tyrosine kinase inhibitor (TKI);    epidermal growth factor receptor (EGFR);    vascular endothelial growth factor receptor-2 (VEGFR-2);    vascular endothelial growth factor (VEGF);    neuropilin-1 (NP-1);   

DOI  :  10.3390/cells11101694

来源: DOAJ

【 摘 要 】

NSCLC treatment includes targeting of EGFR with tyrosine kinase inhibitors (TKIs) such as Erlotinib; however, resistance to TKIs is commonly acquired through T790M EGFR mutations or overexpression of vascular endothelial growth factor receptor-2 (VEGFR-2). We investigated the mechanisms of EGFR-TKI resistance in NSCLC cell lines with EGFR mutations or acquired resistance to Erlotinib. These studies showed upregulated gene and protein expression of VEGF, VEGFR-2, and a VEGF co-receptor neuropilin-1 (NP-1) in Erlotinib-resistant (1.4–5.3-fold) and EGFR double-mutant (L858R and T790M; 4.1–8.3-fold) NSCLC cells compared to parental and EGFR single-mutant (L858R) NSCLC cell lines, respectively. Immunofluorescence and FACS analysis revealed increased expression of VEGFR-2 and NP-1 in EGFR-TKI-resistant cell lines compared to TKI-sensitive cell lines. Cell proliferation assays showed that treatment with a VEGFR-2 inhibitor combined with Erlotinib lowered cell survival in EGFR double-mutant NSCLC cells to 9% compared to 72% after treatment with Erlotinib alone. Furthermore, Kaplan–Meier analysis revealed shorter median survival in late-stage NSCLC patients with high vs. low VEGFR-2 expression (14 mos vs. 21 mos). The results indicate that VEGFR-2 may play a key role in EGFR-TKI resistance and that combined treatment of Erlotinib with a VEGFR-2 inhibitor may serve as an effective therapy in NSCLC patients with EGFR mutations.

【 授权许可】

Unknown