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

doi:10.1371/journal.pone.0232985

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

PLoS One. 2020 May 15;15(5):e0232985. doi: 10.1371/journal.pone.0232985. eCollection 2020.

Authors

Bin Liu¹, Olivia Adaly Diaz Arguello¹, Deng Chen¹, Siwei Chen¹, Ali Saber¹, Hidde J Haisma¹

Affiliation

¹ Department of Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy, Groningen, University of Groningen, Groningen, The Netherlands.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

A549 Cells
Antineoplastic Agents / therapeutic use
Apoptosis / drug effects
Apoptosis / genetics
CRISPR-Cas Systems*
Carcinoma, Renal Cell / genetics
Carcinoma, Renal Cell / pathology
Carcinoma, Renal Cell / therapy*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Proliferation / genetics
Cisplatin / pharmacology
Combined Modality Therapy
Drug Resistance, Neoplasm / genetics
ErbB Receptors / antagonists & inhibitors
ErbB Receptors / genetics
Gene Knockout Techniques / methods*
Genes, erbB-1
HEK293 Cells
HeLa Cells
Humans
Kidney Neoplasms / genetics
Kidney Neoplasms / pathology
Kidney Neoplasms / therapy*
MAP Kinase Signaling System / drug effects
MAP Kinase Signaling System / genetics
Models, Biological
Protein Kinase Inhibitors / therapeutic use
Sunitinib / therapeutic use*

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
EGFR protein, human
ErbB Receptors
Cisplatin
Sunitinib

Grants and funding

Bin Liu and Siwei Chen received financial support from the program of China Scholarship Council (CSC).”