CK2 inhibitor CX-4945 destabilizes NOTCH1 and synergizes with JQ1 against human T-acute lymphoblastic leukemic cells.
Tang, Kevin Charles
Anderson, Nicole M.
Roderick, Justine E.
Kelliher, Michelle A.
Seldin, David C.
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Citation (published version)Haiwei Lian, Dun Li, Yun Zhou, Esther Landesman-Bollag, Guanglan Zhang, Nicole M. Anderson, Kevin Charles Tang, Justine E. Roderick, Michelle A. Kelliher, David C. Seldin, Hui Fu, Hui Feng. 2017. "CK2 inhibitor CX-4945 destabilizes NOTCH1 and synergizes with JQ1 against human T-acute lymphoblastic leukemic cells.." Haematologica, Volume 102, Issue 1, pp. e17 - e21.
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer of developing thymocytes, and remains fatal in 20% of pediatric and 50% of adult patients.1,2 Frequent application of multi-agent cytotoxic drugs leads to disease relapse and high toxicities, underscoring the need for targeted therapies. The suppression of aberrant NOTCH1 signaling in T-ALL cells by gamma secretase inhibitors (GSIs) has been met with much enthusiasm; however, the gastrointestinal toxicities and drug resistance of GSIs restrain their clinical applications.3 The proto-oncogene MYC is a transcriptional target of NOTCH1 and a dominant driver of T-ALL pathogenesis.3 Targeting MYC-mediated transcriptional programs through BET bromodomain inhibitor JQ1 exhibits anti-leukemic efficacy in vitro and in vivo.4 However, global repression of transcription is predicted to cause toxicities. Identification of drug(s) synergizing with JQ1 to kill T-ALL cells may enhance the efficacy while reducing toxicities. Protein kinase CK2 is a tetrameric serine-threonine kinase composed of two catalytic (α or α′) and regulatory (β) subunits that can phosphorylate NOTCH1.5 CK2 inhibition by CX-4945, a potent and specific inhibitor in clinical trials for treating breast cancer and multiple myeloma, significantly reduces growth and survival of human T-ALL cells,6 and down-regulates NOTCH1 in lung cancer cells.7 However, it remains unclear whether the cytotoxic effect of CX-4945 on T-ALL cells is associated with repression of NOTCH1 signaling. Here we show that CK2 inhibition by CX-4945 destabilizes NOTCH1 and synergizes with JQ1 to induce apoptosis in human T-ALL cells, implicating an alternative strategy to target NOTCH1 signaling in refractory/relapsed T-ALL.
Obtained from the Haematologica Journal website http://www.haematologica.org