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

Chike Osude; Leo Lin; Meet Patel; Adam Eckburg; Joseph Berei; Adijan Kuckovic; Namrata Dube; Aayush Rastogi; Shruti Gautam; Thomas J. Smith; Shylendra B. Sreenivassappa; Neelu Puri

doi:10.3390/cells11101694

Cells (May 2022)

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

Chike Osude,
Leo Lin,
Meet Patel,
Adam Eckburg,
Joseph Berei,
Adijan Kuckovic,
Namrata Dube,
Aayush Rastogi,
Shruti Gautam,
Thomas J. Smith,
Shylendra B. Sreenivassappa,
Neelu Puri

Affiliations

Chike Osude: Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, IL 61107, USA
Leo Lin: Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, IL 61107, USA
Meet Patel: Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, IL 61107, USA
Adam Eckburg: Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, IL 61107, USA
Joseph Berei: Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, IL 61107, USA
Adijan Kuckovic: Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, IL 61107, USA
Namrata Dube: Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, IL 61107, USA
Aayush Rastogi: Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, IL 61107, USA
Shruti Gautam: Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, IL 61107, USA
Thomas J. Smith: College of Education, Northern Illinois University, Dekalb, IL 60115, USA
Shylendra B. Sreenivassappa: Department of Hematology/Oncology, OSF Saint Anthony Medical Center, Rockford, IL 61107, USA
Neelu Puri: Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, Rockford, IL 61107, USA

DOI: https://doi.org/10.3390/cells11101694
Journal volume & issue: Vol. 11, no. 10
p. 1694

Abstract

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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.

Published in Cells

ISSN: 2073-4409 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Science: Biology (General): Cytology
Website: https://www.mdpi.com/journal/cells

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