ABC-transporter upregulation mediates resistance to the CDK7 inhibitors THZ1 and ICEC0942.
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Embargo End Date
ICR Authors
Authors
Sava, GP
Fan, H
Fisher, RA
Lusvarghi, S
Pancholi, S
Ambudkar, SV
Martin, L-A
Charles Coombes, R
Buluwela, L
Ali, S
Fan, H
Fisher, RA
Lusvarghi, S
Pancholi, S
Ambudkar, SV
Martin, L-A
Charles Coombes, R
Buluwela, L
Ali, S
Document Type
Journal Article
Date
2020-01-16
Date Accepted
2019-08-24
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 upregulated 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.
Citation
Oncogene, 2020, 39 (3), pp. 651 - 663
Source Title
Publisher
SPRINGERNATURE
ISSN
0950-9232
eISSN
1476-5594
Collections
Research Team
Endocrinology