Imperial College London
Alternate

ProfessorLakiBuluwela

Faculty of Medicine, Department of Surgery & Cancer

Professor of Cancer Medicine
 
 
 
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Contact

 

+44 (0)20 7594 2812l.buluwela

 
 
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Assistant

 

Mrs Maureen Francis +44 (0)20 7594 2793

 
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Location

 

133ICTEM buildingHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Sava:2020:10.1038/s41388-019-1008-y,
author = {Sava, G and Fan, H and Fisher, R and Coombes, R and Buluwela, L and Ali, S},
doi = {10.1038/s41388-019-1008-y},
journal = {Oncogene},
pages = {651--663},
title = {ABC transporter upregulation mediates resistance to the CDK7 inhibitors THZ1 and ICEC0942.},
url = {http://dx.doi.org/10.1038/s41388-019-1008-y},
volume = {39},
year = {2020}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - The CDK7 inhibitors (CDK7i) ICEC0942 and THZ1, are promising new cancer therapeutics. Resistance to targeted drugs frequently compromises cancer treatment. We sought to identify mechanisms by which cancer cells may become resistant to CDK7i. Resistant lines were established through continuous drug selection. ABC-transporter copy number, expression and activity were examined using real-time PCR, immunoblotting and flow cytometry. Drug responses were measured using growth assays. ABCB1 was up-regulated in ICEC0942-resistant cells and there was cross-resistance to THZ1. THZ1-resistant cells upregulated ABCG2 but remained sensitive to ICEC0942. Drug resistance in both cell lines was reversible upon inhibition of ABC-transporters. CDK7i response was altered in adriamycin- and mitoxantrone-resistant cell lines demonstrating ABC-transporter upregulation. ABCB1 expression correlated with ICEC0942 and THZ1 response, and ABCG2 expression with THZ2 response, in a panel of cancer cell lines. We have identified ABCB1 upregulation as a common mechanism of resistance to ICEC0942 and THZ1, and confirmed that ABCG2 upregulation is a mechanism of resistance to THZ1. The identification of potential mechanisms of CDK7i resistance and differences in susceptibility of ICEC0942 and THZ1 to ABC-transporters, may help guide their future clinical use.
AU  - Sava,G
AU  - Fan,H
AU  - Fisher,R
AU  - Coombes,R
AU  - Buluwela,L
AU  - Ali,S
DO  - 10.1038/s41388-019-1008-y
EP  - 663
PY  - 2020///
SN  - 0950-9232
SP  - 651
TI  - ABC transporter upregulation mediates resistance to the CDK7 inhibitors THZ1 and ICEC0942.
T2  - Oncogene
UR  - http://dx.doi.org/10.1038/s41388-019-1008-y
UR  - https://www.nature.com/articles/s41388-019-1008-y
UR  - http://hdl.handle.net/10044/1/73017
VL  - 39
ER  -
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