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      Pan-CDK inhibition augments cisplatin lethality in nasopharyngeal carcinoma cell lines and xenograft models

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          Abstract

          In addition to their canonical roles in regulating cell cycle transition and transcription, cyclin-dependent kinases (CDKs) have been shown to coordinate DNA damage response pathways, suggesting a rational pairing of CDK inhibitors with genotoxic chemotherapeutic agents in the treatment of human malignancies. Here, we report that roniciclib (BAY1000394), a potent pan-CDK inhibitor, displays promising anti-neoplastic activity as a single agent and potentiates cisplatin lethality in preclinical nasopharyngeal carcinoma (NPC) models. Proliferation of the NPC cell lines HONE-1, CNE-2, C666-1, and HK-1 was effectively curbed by roniciclib treatment, with IC 50 values between 11 and 38 nmol/L. These anticancer effects were mediated by pleiotropic mechanisms consistent with successful blockade of cell cycle CDKs 1, 2, 3, and 4 and transcriptional CDKs 7 and 9, ultimately resulting in arrest at G1/S and G2/M, downregulation of the transcriptional apparatus, and repression of anti-apoptotic proteins. Considerably enhanced tumor cell apoptosis was achieved following combined treatment with 10 nmol/L roniciclib and 2.0 μmol/L cisplatin; this combination therapy achieved a response over 250% greater than either drug alone. Although roniciclib chemosensitized NPC cells to cisplatin, it did not sensitize untransformed (NP69) cells. The administration of 0.5 mg/kg roniciclib to BALB/c xenograft mice was well tolerated and effectively restrained tumor growth comparable to treatment with 6 mg/kg cisplatin, whereas combining these two agents produced far greater tumor suppression than either of the monotherapies. In summary, these data demonstrate that roniciclib has strong anti-NPC activity and synergizes with cisplatin chemotherapy at clinically relevant doses, thus justifying further evaluation of this combinatorial approach in clinical settings.

          Cancer: Cell cycle–blocking drug active against throat cancer

          Nasopharyngeal carcinoma (NPC) is an uncommon malignancy arising from the nasopharynx epithelium, and is endemic to east and southeast parts of Asia where they account for 70% of worldwide incidence. Researchers from the Cancer Science Institute of Singapore examined the anti-tumor effects of roniciclib a small-molecule drug that blocks a family of enzymes known as cyclin-dependent kinases (CDKs) which are classically involved in cell cycle progression and transcription—in cell lines and mouse models of nasopharyngeal carcinoma. Because CDK/cyclin complexes have a putative role in DNA repair, roniciclib was combined with cisplatin, a DNA-damaging agent which is currently used in chemotherapy of NPC. The authors found that roniciclib had potent anti-NPC effects when given alone, whereas the combination of roniciclib and cisplatin proved to be highly synergistic and restrained tumor growth to a greater extent than either drugs given alone. Interestingly, roniciclib appeared to selectively enhance the anti-cancer effects of cisplatin in cancerous cells while this “chemo-sensitizing” phenomenon was not seen in non-cancerous cells, suggesting that giving both drugs together could improve the effectiveness of standard chemotherapy without incurring additional toxicities. These findings suggest that roniciclib should be evaluated clinically in patients with NPC.

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          Most cited references 27

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          The genomic landscape of nasopharyngeal carcinoma.

          Nasopharyngeal carcinoma (NPC) has extremely skewed ethnic and geographic distributions, is poorly understood at the genetic level and is in need of effective therapeutic approaches. Here we determined the mutational landscape of 128 cases with NPC using whole-exome and targeted deep sequencing, as well as SNP array analysis. These approaches revealed a distinct mutational signature and nine significantly mutated genes, many of which have not been implicated previously in NPC. Notably, integrated analysis showed enrichment of genetic lesions affecting several important cellular processes and pathways, including chromatin modification, ERBB-PI3K signaling and autophagy machinery. Further functional studies suggested the biological relevance of these lesions to the NPC malignant phenotype. In addition, we uncovered a number of new druggable candidates because of their genomic alterations. Together our study provides a molecular basis for a comprehensive understanding of, and exploring new therapies for, NPC.
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            Cdc2-cyclin E complexes regulate the G1/S phase transition.

            The cyclin-dependent kinase inhibitor p27(Kip1) is known as a negative regulator of cell-cycle progression and as a tumour suppressor. Cdk2 is the main target of p27 (refs 2, 3) and therefore we hypothesized that loss of Cdk2 activity should modify the p27(-/-) mouse phenotype. Here, we show that although p27(-/-) Cdk2(-/-) mice developed ovary tumours and tumours in the anterior lobe of the pituitary, we failed to detect any functional complementation in p27(-/-) Cdk2(-/-) double-knockout mice, indicating a parallel pathway regulated by p27. We observed elevated levels of S phase and mitosis in tissues of p27(-/-) Cdk2(-/-) mice concomitantly with elevated Cdc2 activity in p27(-/-) Cdk2(-/-) extracts. p27 binds to Cdc2, cyclin B1, cyclin A2, or suc1 complexes in wild-type and Cdk2(-/-) extracts. In addition, cyclin E binds to and activates Cdc2. Our in vivo results provide strong evidence that Cdc2 may compensate the loss of Cdk2 function.
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              Nasopharyngeal carcinoma.

               A.T.C. Chan (2010)
              With the improvement in local control achieved by more precise imaging and radiotherapy, the predominant mode of failure for nasopharyngeal carcinoma is distant metastases. Concurrent cisplatin-radiotherapy with or without adjuvant chemotherapy is the standard treatment approach for stages IIB and above disease. The addition of neoadjuvant chemotherapy has been most promising, and phase III trial results are awaited. Quantitative Epstein-Barr virus (EBV) DNA can be applied clinically for disease monitoring and follow-up, and may in future be used for risk stratification strategies. Targeted therapies against epidermal growth factor receptor and angiogenesis have demonstrated activity, and immunotherapeutic approaches are being investigated.
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                Author and article information

                Contributors
                +65 6779 5555 , phcgbc@nus.edu.sg
                Journal
                Signal Transduct Target Ther
                Signal Transduct Target Ther
                Signal Transduction and Targeted Therapy
                Nature Publishing Group UK (London )
                2095-9907
                2059-3635
                13 April 2018
                13 April 2018
                2018
                : 3
                Affiliations
                [1 ]ISNI 0000 0001 2180 6431, GRID grid.4280.e, Cancer Science Institute of Singapore, , National University of Singapore, ; Singapore, Singapore
                [2 ]GRID grid.440782.d, Department of Haematology-Oncology, , National University Cancer Institute, ; Singapore, Singapore
                [3 ]ISNI 0000 0004 0451 6143, GRID grid.410759.e, Department of Pharmacology, Yong Loo Lin School of Medicine, , National University Health System, ; Singapore, Singapore
                [4 ]ISNI 0000 0004 0451 6143, GRID grid.410759.e, Department of Otolaryngology-Head and Neck Surgery, , National University Health System, ; Singapore, Singapore
                [5 ]ISNI 0000 0004 0374 4101, GRID grid.420044.6, Drug Discovery, TRG Oncology, , Bayer Pharma AG, ; Berlin, Germany
                Article
                10
                10.1038/s41392-018-0010-0
                5897350
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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