CRISPR-mediated ablation of overexpressed EGFR in combination with sunitinib significantly suppresses renal cell carcinoma proliferation

Bin Liu, Olivia Adaly Diaz Arguello, Deng Chen, Siwei Chen, Ali Saber, Hidde J Haisma*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Receptor tyrosine kinases, such as VEGFR, PDGFR and EGFR, play important roles in renal cancer. In this study, we investigated EGFR knockout as a therapeutic approach in renal cell carcinoma (RCC). We showed that a renal cell carcinoma cell line (RC21) has higher expression of EGFR as compared to other frequently used cell lines such as HEK293, A549, Hela and DLD1. Ablation of EGFR by CRISPR/Cas9 significantly restrained tumor cell growth and activated the MAPK (pERK1/2) pathway. The VEGFR and PDGFR inhibitor, sunitinib, attenuated the expression of MAPK (pERK1/2) and pAKT induced by EGFR loss and further inhibited EGFR(-/-) cell proliferation. We showed that loss of EGFR eventually leads to resistance to SAHA and cisplatin. Furthermore, EGFR loss induced G2/M phase arrest and resulted in an increased resistance to TNF-related apoptosis-inducing ligand (TRAIL) in renal cell carcinoma. Thus, ablation of overexpressed EGFR by CRISPR/Cas9 alone or in combination with sunitinib may be a new treatment option for renal cell carcinoma.

Original languageEnglish
Article number0232985
Number of pages13
JournalPLoS ONE
Volume15
Issue number5
DOIs
Publication statusPublished - 15-May-2020

Keywords

  • INHIBITION
  • RESISTANCE
  • TRAIL
  • MECHANISMS
  • GEFITINIB
  • SURVIVAL
  • THERAPY
  • CANCER
  • VEGFR

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