ABC transporter upregulation mediates resistance to the CDK7 inhibitors THZ1 and ICEC0942.

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Title: ABC transporter upregulation mediates resistance to the CDK7 inhibitors THZ1 and ICEC0942.
Authors: Sava, G
Fan, H
Fisher, R
Coombes, R
Buluwela, L
Ali, S
Item Type: Journal Article
Abstract: 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.
Issue Date: 17-Sep-2019
Date of Acceptance: 24-Aug-2019
URI: http://hdl.handle.net/10044/1/73017
ISSN: 0950-9232
Publisher: Springer Nature [academic journals on nature.com]
Journal / Book Title: Oncogene
Sponsor/Funder: Cancer Research UK
Cancer Research UK
Funder's Grant Number: 9335
12011
Keywords: Oncology & Carcinogenesis
1112 Oncology and Carcinogenesis
1103 Clinical Sciences
Publication Status: Accepted
Embargo Date: 2020-03-17
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine



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