Imperial College London
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DrAdamFrampton

Faculty of Medicine, Department of Surgery & Cancer

Honorary Clinical Lecturer
 
 
 
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Contact

 

+44 (0)20 7594 2125a.frampton

 
 
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Location

 

4005Institute of Reproductive and Developmental BiologyHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Van:2020:10.1002/jcp.29463,
author = {Van, Der Steen N and Keller, K and Dekker, H and Porcelli, L and Honeywell, RJ and Van, Meerloo J and Musters, RJP and Kathmann, I and Frampton, AE and Liu, DSK and Ruijtenbeek, R and Rolfo, C and Pauwels, P and Giovannetti, E and Peters, GJ},
doi = {10.1002/jcp.29463},
journal = {Journal of Cellular Physiology},
pages = {8085--8097},
title = {Crizotinib sensitizes the erlotinib resistant HCC827GR5 cell line by influencing lysosomal function},
url = {http://dx.doi.org/10.1002/jcp.29463},
volume = {235},
year = {2020}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - In nonsmall cell lung cancer, sensitizing mutations in epidermal growth factor receptor (EGFR) or cMET amplification serve as good biomarkers for targeted therapies against EGFR or cMET, respectively. Here we aimed to determine how this different genetic background would affect the interaction between the EGFRinhibitor erlotinib and the cMETinhibitor crizotinib. To unravel the mechanism of synergy we investigated the effect of the drugs on various parameters, including cell cycle arrest, migration, protein phosphorylation, kinase activity, the expression of drug efflux pumps, intracellular drug concentrations, and livecell microscopy. We observed additive effects in EBC1, H1975, and HCC827, and a strong synergism in the HCC827GR5 cell line. This cell line is a clone of the HCC827 cells that harbor an EGFR exon 19 deletion and has been made resistant to the EGFRinhibitor gefitinib, resulting in cMET amplification. Remarkably, the intracellular concentration of crizotinib was significantly higher in HCC827GR5 compared to the parental HCC827 cell line. Furthermore, livecell microscopy with a pHsensitive probe showed a differential reaction of the pH in the cytoplasm and the lysosomes after drug treatment in the HCC827GR5 in comparison with the HCC827 cells. This change in pH could influence the process of lysosomal sequestration of drugs. These results led us to the conclusion that lysosomal sequestration is involved in the strong synergistic reaction of the HCC827GR5 cell line to crizotinib–erlotinib combination. This finding warrants future clinical studies to evaluate whether genetic background and lysosomal sequestration could guide tailored therapeutic interventions.
AU  - Van,Der Steen N
AU  - Keller,K
AU  - Dekker,H
AU  - Porcelli,L
AU  - Honeywell,RJ
AU  - Van,Meerloo J
AU  - Musters,RJP
AU  - Kathmann,I
AU  - Frampton,AE
AU  - Liu,DSK
AU  - Ruijtenbeek,R
AU  - Rolfo,C
AU  - Pauwels,P
AU  - Giovannetti,E
AU  - Peters,GJ
DO  - 10.1002/jcp.29463
EP  - 8097
PY  - 2020///
SN  - 0021-9541
SP  - 8085
TI  - Crizotinib sensitizes the erlotinib resistant HCC827GR5 cell line by influencing lysosomal function
T2  - Journal of Cellular Physiology
UR  - http://dx.doi.org/10.1002/jcp.29463
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000508127400001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - https://onlinelibrary.wiley.com/doi/10.1002/jcp.29463
UR  - http://hdl.handle.net/10044/1/83793
VL  - 235
ER  -
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