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CDK9 as a potential molecular target in NK cell leukemia/lymphoma
investigations and the present studies suggest a great advantage for the clinical use of CDK9 inhibitors. Future investigation is needed to analyze the status of regulatory elements after BAY 1143572 treatment.
In the present study, we have established a mouse xeno- geneic model for pre-clinical testing of a CDK9/P-TEFb inhibitor. Severe immune deficiencies in NOG mice per- mit engraftment of human immune cells, where they may retain very similar functions in an in vivo environment that can be manipulated experimentally.41,42 In these mice, pri- mary EBV-positive, CD16/CD56-positive, CD3– and CD19-negative cells from ANKL patients were found to robustly infiltrate several organs such as the spleen, liver and bone marrow. These features are very similar to those seen in the ANKL patients who donated the cells. To the best of our knowledge, this is the first report of pri- mary ANKL cell-bearing mice in which it could be shown that ANKL cells are maintained by serial transplantations. This is a useful model because these tumor cells cannot be cultured as cell lines in vitro, implying that the in vivo microenvironment is an absolute requirement for tumor cell survival. Hence, our present in vivo ANKL model rep- resents the in vivo human ANKL environment better than other models using established tumor cell lines. Thus, this in vivo xenogeneic primary tumor model offers a useful methodology for probing ANKL pathogenesis and pro- vides a more relevant tool for testing novel antitumor agents. Here, we report that BAY 1143572 possesses strong antitumor activity, as demonstrated in vivo by reduced ANKL cell infiltration into blood, bone marrow, liver and spleen in this model. Moreover, this model also allowed us to demonstrate that BAY 1143572 monothera- py can prolong survival of ANKL-bearing hosts. It should also be noted that the in vivo antitumor activity of BAY 1143572 in the primary tumor cell-bearing NOG mice was actually mediated by the on-target effect of BAY 1143572; namely, the inhibition of CDK9 and subsequent inhibition of phosphorylation at the Ser2 site of the RNAPII CTD was clearly demonstrated in our previous study on ATL.17 It is also important to note that no BAY 1143572 toxicity was observed in any of the mice studied here. Taken together, these findings in the primary ANKL mice strong- ly suggest that targeting CDK9 in human ANKL patients
could be a promising therapeutic approach.
To the best of our knowledge, this is the first report
evaluating the efficacy of CDK9-targeted therapy in NK- cell leukemia/lymphoma, including ANKL. It must be noted that several other anti-cancer agents targeting CDK9 have already been tested in the clinic, but with little benefit and they were accompanied by numerous adverse events.43-47 The latter may have been due to their insuffi- cient selectivity for CDK9.48 In contrast, BAY 1143572 exhibits marked selectivity for CDK9/PTEFb,21 and pos- sesses strong antitumor effects against NK-cell leukemia/lymphoma including ANKL, not only in vitro, but also in animal models in vivo. Because, in clinical prac- tice, NK-cell leukemia/lymphoma is highly aggressive and refractory, combination strategies such as CDK9 inhibi- tion together with PD-1 blockade should be worth consid- ering.49,50
In conclusion, we propose that BAY 1143572 holds great promise as a potential agent to treat NK-cell leukemia/lymphoma, including ANKL patients. The mechanism of action is via CDK9/P-TEFb inhibition. Clinical evaluation of CDK9/P-TEFb selective inhibitors in patients with NK cell leukemia/lymphoma is therefore warranted.
Acknowledgments
We thank Ms Chiori Fukuyama for excellent technical assis- tance and Ms Naomi Ochiai for excellent secretarial assistance. We also thank Stuart Ince (Bayer US, LLC) for the kind contri- bution of obtaining BAY 1143572.
Funding
This work was supported by research funding from Bayer AG to Nagoya City University Graduate School of Medical Sciences. This work was also supported by grants-in-aid for scientific research (B) (No. 16H04713 to Takashi Ishida), grants-in-aid from the National Cancer Center Research and Development Fund (Nos. 29-A-3 to Takashi Ishida, and Shinsuke Iida), and grants-in-aid from the Japan Agency for Medical Research and Development (Nos. 17ck0106287h0001 to Takashi Ishida, 16cm0106301h0001 to Takashi Ishida, and 15ck0106132h0002 to Takashi Ishida, Ryuzu Ueda, and Shinsuke Iida).
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