Inhibition of VEGFR2 and EGFR signaling cooperatively suppresses the proliferation of oral squamous cell carcinoma

Author:

Onda Maho1,Ota Akinobu23ORCID,Ito Kunihiro1,Ono Takayuki1,Karnan Sivasundaram2ORCID,Kato Mikako1,Kondo Sayuri1,Furuhashi Akifumi1,Hayashi Tomio1,Hosokawa Yoshitaka2,Kazaoka Yoshiaki1

Affiliation:

1. Department of Oral and Maxillofacial Surgery Aichi Medical University Hospital Nagakute Japan

2. Department of Biochemistry Aichi Medical University School of Medicine Nagakute Japan

3. Department of Food and Nutritional Environment College of Human Life and Environment Kinjo Gakuin University Nagoya Japan

Abstract

AbstractBackgroundEpidermal growth factor receptor (EGFR) is frequently overexpressed in oral squamous cell carcinoma (OSCC), and EGFR‐targeting therapeutics have been widely employed to treat patients with a variety of carcinomas including OSCC. Here, we aimed to investigate alternative signaling for OSCC survival under the disruption of EGFR signaling.MethodsOSCC cell lines, namely HSC‐3 and SAS, were utilized to investigate how EGFR disruption affects cell proliferation. Gene set enrichment analysis was performed to examine how EGFR disruption affects oncogenic signaling in OSCC cells. Disruption of KDR gene was performed using CRISPR/Cas9 techniques. A VEGFR inhibitor, vatalanib was used to research the impact of VEGFR inhibition on OSCC survival.ResultsEGFR disruption significantly decreased the proliferation and oncogenic signaling including Myc and PI3K‐Akt, in OSCC cells. Chemical library screening assays revealed that VEGFR inhibitors continued to inhibit the proliferation of EGFR‐deficient OSCC cells. In addition, CRISPR‐mediated disruption of KDR/VEGFR2 retarded OSCC cell proliferation. Furthermore, combined erlotinib–vatalanib treatment exhibited a more potent anti‐proliferative effect on OSCC cells, compared to either monotherapy. The combined therapy effectively suppressed the phosphorylation levels of Akt but not p44/42.ConclusionVEGFR‐mediated signaling would be an alternative signaling pathway for the survival of OSCC cells under the disruption of EGFR signaling. These results highlight the clinical application of VEGFR inhibitors in the development of multi‐molecular‐targeted therapeutics against OSCC.

Publisher

Wiley

Subject

Cancer Research,Radiology, Nuclear Medicine and imaging,Oncology

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