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Overexpression of ATP‐binding cassette transporter ABCG2 mediates acquired resistance LDC000067, a selective inhibitor of cyclin‐dependent kinase CDK9
Author(s) -
Lin MingLu,
Wu ChungPu
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.936.8
Subject(s) - abcg2 , cyclin dependent kinase 9 , drug resistance , kinase , cancer research , pharmacology , atp binding cassette transporter , chemistry , biology , transporter , biochemistry , protein kinase a , cyclin dependent kinase 2 , gene , microbiology and biotechnology
The serine/threonine cyclin‐dependent kinase 9 (CDK9) is a critical elongation factor for RNA polymerase II‐directed transcription, which is important for cancer cell survival. Recently, CDK9 has emerged as a valid therapeutic target for cancer, and many CDK9 inhibitors have been investigated. LDC000067 is a novel small molecule compound that selectively and potently inhibits the activity of CDK9. However, alike most therapeutic drugs, the risk of developing drug resistance to LDC000067 presents a therapeutic challenge. Since the overexpression of ATP‐binding cassette (ABC) drug transporter ABCG2 is one of the most common mechanisms of drug resistance, we thus investigated the effect of ABCG2 on the cellular efficacy of LDC000067. In this study, we discovered that ABCG2‐overexpressing cancer cells and cells transfected with wild‐type ABCG2 were highly resistant to LDC000067. The inhibitory activity of LDC000067 was significantly reduced by the function of ABCG2. More importantly, we found that by inhibiting the function of ABCG2, the reduced apoptosis and sensitivity to LDC000067 treatment in ABCG2‐overexpressing cells can be restored. In conclusion, the development of ABCG2‐mediated drug resistance to LDC000067 in cancer poses a significant therapeutic challenge, and a combination therapy of LDC000067 with a modulator of ABCG2 should be further investigated as a potential treatment approach.