Cyclin-dependent kinase 9 is a novel specific molecular target in adult T-cell leukemia/lymphoma.

Abstract

Cyclin-dependent kinase 9 (CDK9), a subunit of the positive transcription elongation factor b (P-TEFb) complex, regulates gene transcription elongation by phosphorylating the C-terminal domain (CTD) of RNA polymerase II (RNAPII). The deregulation of CDK9/P-TEFb has important implications for many cancer types. BAY 1143572 is a novel and highly selective CDK9/P-TEFb inhibitor currently being investigated in phase 1 studies. We evaluated the therapeutic potential of BAY 1143572 in adult T-cell leukemia/lymphoma (ATL). As a result of CDK9 inhibition and subsequent inhibition of phosphorylation at serine 2 of the RNAPII CTD, BAY 1143572 decreased c-Myc and Mcl-1 levels in ATL-derived or human T-cell lymphotropic virus type-1 (HTLV-1)-transformed lines and primary ATL cells tested, leading to their growth inhibition and apoptosis. Median inhibitory concentrations for BAY 1143572 in ATL-derived or HTLV-1-transformed lines (n = 8), primary ATL cells (n = 11), and CD4+ cells from healthy volunteers (n = 5) were 0.535, 0.30, and 0.36 μM, respectively. Next, NOG mice were used as recipients of tumor cells from an ATL patient. BAY 1143572-treated ATL-bearing mice (once daily 12.5 mg/kg oral application) demonstrated significantly decreased ATL cell infiltration of the liver and bone marrow, as well as decreased human soluble interleukin-2 receptor levels in serum (reflecting the ATL tumor burden), compared with untreated mice (n = 8 for both). BAY 1143572-treated ATL-bearing mice demonstrated significantly prolonged survival compared with untreated ATL-bearing mice (n = 7 for both). Collectively, this study indicates that BAY 1143572 showed strong potential as a novel treatment of ATL.

DOI: 10.1182/blood-2016-09-741983

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Cite this paper

@article{Narita2017CyclindependentK9, title={Cyclin-dependent kinase 9 is a novel specific molecular target in adult T-cell leukemia/lymphoma.}, author={Tomoko Narita and Takashi Ishida and Asahi Ito and Ayako Masaki and Shiori Kinoshita and Susumu Suzuki and Hisashi Takino and Takashi Yoshida and Masaki Ri and Shigeru Kusumoto and Hirokazu Komatsu and Kazunori Imada and Yuetsu Tanaka and Akifumi Takaori-Kondo and Hiroshi Inagaki and Arne Scholz and Philip Lienau and Taruho S. Kuroda and Ryuzo Ueda and Shinsuke Iida}, journal={Blood}, year={2017}, volume={130 9}, pages={1114-1124} }