nach oben

Cancer Chemotherapy and Pharmacology

Erschienen in:

11.04.2020 | Original Article

Inhibition of cyclin-dependent kinases by AT7519 enhances nasopharyngeal carcinoma cell response to chemotherapy

verfasst von: Xin Wei, Jiabin Nian, Jing Zheng, Yangli He, Min Zeng

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 5/2020

Einloggen, um Zugang zu erhalten

Abstract

Background

The poor outcomes in nasopharyngeal carcinoma (NPC) necessitate new treatments. AT7519 is a potent inhibitor of several cyclin-dependent kinases (CDKs) and is currently in the early phase of clinical development for cancer treatment. The potent anti-cancer activities of AT7519 have been reported in various cancers, but not in NPC.

Materials and methods

The effects of AT7519 in NPC were systematically analyzed using cell culture assays and xenograft mouse models. The effects of AT7519 on molecules involved in mRNA transcription were examined.

Results

AT7519, at a nanomolar concentration, significantly inhibits growth via arresting cells at G2/M phase, and induces apoptosis in NPC cells regardless of Epstein–Barr virus (EBV) infection and cellular origin. It also inhibits growth of a subpopulation of cells with highly proliferative and invasive features. Importantly, AT7519 acts synergistically with cisplatin and is effective against chemo-resistant NPC cells. Mechanistically, AT7519 inhibits phosphorylation of Rb, suggesting the inhibition of CDK2 in NPC. It also decreases N-myc level and RNA polymerase II phosphorylation, and inhibits transcription. Consistent with the in vitro findings, we demonstrate that AT7519 is effective as a single agent in two independent NPC xenograft mouse models. The combination of ATP7519 and cisplatin results in greater efficacy than cisplatin alone in inhibiting NPC tumor growth.

Conclusions

Our work is the first to report anti-NPC activities of AT7519. Our preclinical evidence suggests that AT7519 is a useful addition to overcome NPC chemo-resistance.

Nur mit Berechtigung zugänglich

Cao SM, Simons MJ, Qian CN (2011) The prevalence and prevention of nasopharyngeal carcinoma in China. Chin J Cancer 30(2):114–119CrossRef

Lee AW, Ng WT, Chan LL, Hung WM, Chan CC, Sze HC, Chan OS, Chang AT, Yeung RM (2014) Evolution of treatment for nasopharyngeal cancer: success and setback in the intensity-modulated radiotherapy era. Radiother Oncol 110(3):377–384. https://doi.org/10.1016/j.radonc.2014.02.003 CrossRefPubMed

Zhang L, MacIsaac KD, Zhou T, Huang PY, Xin C, Dobson JR, Yu K, Chiang DY, Fan Y, Pelletier M, Wang Y, Jaeger S, Krishnamurthy Radhakrishnan V, JeBailey L, Skewes-Cox P, Zhang J, Fang W, Huang Y, Zhao H, Zhao Y, Li E, Peng B, Huang A, Dranoff G, Hammerman PS, Engelman J, Bitter H, Zeng YX, Yao Y (2017) Genomic analysis of nasopharyngeal carcinoma reveals TME-based subtypes. Mol Cancer Res 15(12):1722–1732. https://doi.org/10.1158/1541-7786.MCR-17-0134 CrossRefPubMed

Dai W, Zheng H, Cheung AK, Lung ML (2016) Genetic and epigenetic landscape of nasopharyngeal carcinoma. Chin Clin Oncol 5(2):16. https://doi.org/10.21037/cco.2016.03.06 CrossRefPubMed

Blanchard P, Lee A, Marguet S, Leclercq J, Ng WT, Ma J, Chan AT, Huang PY, Benhamou E, Zhu G, Chua DT, Chen Y, Mai HQ, Kwong DL, Cheah SL, Moon J, Tung Y, Chi KH, Fountzilas G, Zhang L, Hui EP, Lu TX, Bourhis J, Pignon JP, Group M-NC (2015) Chemotherapy and radiotherapy in nasopharyngeal carcinoma: an update of the MAC-NPC meta-analysis. Lancet Oncol 16(6):645–655. https://doi.org/10.1016/S1470-2045(15)70126-9 CrossRefPubMed

Pan ST, Li ZL, He ZX, Qiu JX, Zhou SF (2016) Molecular mechanisms for tumour resistance to chemotherapy. Clin Exp Pharmacol Physiol 43(8):723–737. https://doi.org/10.1111/1440-1681.12581 CrossRefPubMed

Kachalaki S, Ebrahimi M, Mohamed Khosroshahi L, Mohammadinejad S, Baradaran B (2016) Cancer chemoresistance; biochemical and molecular aspects: a brief overview. Eur J Pharm Sci 89:20–30. https://doi.org/10.1016/j.ejps.2016.03.025 CrossRefPubMed

Syn NL, Lim PL, Kong LR, Wang L, Wong AL, Lim CM, Loh TKS, Siemeister G, Goh BC, Hsieh WS (2018) Pan-CDK inhibition augments cisplatin lethality in nasopharyngeal carcinoma cell lines and xenograft models. Signal Transduct Target Ther 3:9. https://doi.org/10.1038/s41392-018-0010-0 CrossRefPubMedPubMedCentral

Li W, Zhao XL, Shang SQ, Shen HQ, Chen X (2015) Dual inhibition of Cdc7 and Cdk9 by PHA-767491 suppresses hepatocarcinoma synergistically with 5-fluorouracil. Curr Cancer Drug Targets 15(3):196–204CrossRef

10.

Wyatt PG, Woodhead AJ, Berdini V, Boulstridge JA, Carr MG, Cross DM, Davis DJ, Devine LA, Early TR, Feltell RE, Lewis EJ, McMenamin RL, Navarro EF, O'Brien MA, O'Reilly M, Reule M, Saxty G, Seavers LC, Smith DM, Squires MS, Trewartha G, Walker MT, Woolford AJ (2008) Identification of N-(4-piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxamide (AT7519), a novel cyclin dependent kinase inhibitor using fragment-based X-ray crystallography and structure-based drug design. J Med Chem 51(16):4986–4999. https://doi.org/10.1021/jm800382h CrossRefPubMed

11.

Dolman ME, Poon E, Ebus ME, den Hartog IJ, van Noesel CJ, Jamin Y, Hallsworth A, Robinson SP, Petrie K, Sparidans RW, Kok RJ, Versteeg R, Caron HN, Chesler L, Molenaar JJ (2015) Cyclin-dependent kinase inhibitor AT7519 as a potential drug for MYCN-dependent neuroblastoma. Clin Cancer Res 21(22):5100–5109. https://doi.org/10.1158/1078-0432.CCR-15-0313 CrossRefPubMedPubMedCentral

12.

Squires MS, Feltell RE, Wallis NG, Lewis EJ, Smith DM, Cross DM, Lyons JF, Thompson NT (2009) Biological characterization of AT7519, a small-molecule inhibitor of cyclin-dependent kinases, in human tumor cell lines. Mol Cancer Ther 8(2):324–332. https://doi.org/10.1158/1535-7163.MCT-08-0890 CrossRefPubMed

13.

Chen EX, Hotte S, Hirte H, Siu LL, Lyons J, Squires M, Lovell S, Turner S, McIntosh L, Seymour L (2014) A Phase I study of cyclin-dependent kinase inhibitor, AT7519, in patients with advanced cancer: NCIC Clinical Trials Group IND 177. Br J Cancer 111(12):2262–2267. https://doi.org/10.1038/bjc.2014.565 CrossRefPubMedPubMedCentral

14.

Mahadevan D, Plummer R, Squires MS, Rensvold D, Kurtin S, Pretzinger C, Dragovich T, Adams J, Lock V, Smith DM, Von Hoff D, Calvert H (2011) A phase I pharmacokinetic and pharmacodynamic study of AT7519, a cyclin-dependent kinase inhibitor in patients with refractory solid tumors. Ann Oncol 22(9):2137–2143. https://doi.org/10.1093/annonc/mdq734 CrossRefPubMed

15.

Gao CF, Xie Q, Su YL, Koeman J, Khoo SK, Gustafson M, Knudsen BS, Hay R, Shinomiya N, Vande Woude GF (2005) Proliferation and invasion: plasticity in tumor cells. Proc Natl Acad Sci USA 102(30):10528–10533. https://doi.org/10.1073/pnas.0504367102 CrossRefPubMed

16.

Squires MS, Cooke L, Lock V, Qi W, Lewis EJ, Thompson NT, Lyons JF, Mahadevan D (2010) AT7519, a cyclin-dependent kinase inhibitor, exerts its effects by transcriptional inhibition in leukemia cell lines and patient samples. Mol Cancer Ther 9(4):920–928. https://doi.org/10.1158/1535-7163.MCT-09-1071 CrossRefPubMed

17.

Chan SY, Choy KW, Tsao SW, Tao Q, Tang T, Chung GT, Lo KW (2008) Authentication of nasopharyngeal carcinoma tumor lines. Int J Cancer 122(9):2169–2171. https://doi.org/10.1002/ijc.23374 CrossRefPubMed

18.

Chou TC (2010) Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res 70(2):440–446. https://doi.org/10.1158/0008-5472.CAN-09-1947 CrossRefPubMed

19.

Chi Y, Welcker M, Hizli AA, Posakony JJ, Aebersold R, Clurman BE (2008) Identification of CDK2 substrates in human cell lysates. Genome Biol 9(10):R149. https://doi.org/10.1186/gb-2008-9-10-r149 CrossRefPubMedPubMedCentral

20.

Chen TJ, Lee SW, Lin LC, Lin CY, Chang KY, Li CF (2014) Cyclin-dependent kinase 4 overexpression is mostly independent of gene amplification and constitutes an independent prognosticator for nasopharyngeal carcinoma. Tumour Biol 35(7):7209–7216. https://doi.org/10.1007/s13277-014-1884-2 CrossRefPubMed

21.

Fornari F, Gramantieri L, Ferracin M, Veronese A, Sabbioni S, Calin GA, Grazi GL, Giovannini C, Croce CM, Bolondi L, Negrini M (2008) MiR-221 controls CDKN1C/p57 and CDKN1B/p27 expression in human hepatocellular carcinoma. Oncogene 27(43):5651–5661. https://doi.org/10.1038/onc.2008.178 CrossRefPubMed

22.

Hsieh WS, Soo R, Peh BK, Loh T, Dong D, Soh D, Wong LS, Green S, Chiao J, Cui CY, Lai YF, Lee SC, Mow B, Soong R, Salto-Tellez M, Goh BC (2009) Pharmacodynamic effects of seliciclib, an orally administered cell cycle modulator, in undifferentiated nasopharyngeal cancer. Clin Cancer Res 15(4):1435–1442. https://doi.org/10.1158/1078-0432.CCR-08-1748 CrossRefPubMed

23.

Kang MA, Kim W, Jo HR, Shin YJ, Kim MH, Jeong JH (2018) Anticancer and radiosensitizing effects of the cyclin-dependent kinase inhibitors, AT7519 and SNS032, on cervical cancer. Int J Oncol 53(2):703–712. https://doi.org/10.3892/ijo.2018.4424 CrossRefPubMed

24.

Schettini F, De Santo I, Rea CG, De Placido P, Formisano L, Giuliano M, Arpino G, De Laurentiis M, Puglisi F, De Placido S, Del Mastro L (2018) CDK 4/6 inhibitors as single agent in advanced solid tumors. Front Oncol 8:608. https://doi.org/10.3389/fonc.2018.00608 CrossRefPubMedPubMedCentral

25.

Roskoski R Jr (2019) Cyclin-dependent protein serine/threonine kinase inhibitors as anticancer drugs. Pharmacol Res 139:471–488. https://doi.org/10.1016/j.phrs.2018.11.035 CrossRefPubMed

26.

Landry BD, Mapa CE, Arsenault HE, Poti KE, Benanti JA (2014) Regulation of a transcription factor network by Cdk1 coordinates late cell cycle gene expression. EMBO J 33(9):1044–1060. https://doi.org/10.1002/embj.201386877 CrossRefPubMedPubMedCentral

27.

Shim EY, Walker AK, Shi Y, Blackwell TK (2002) CDK-9/cyclin T (P-TEFb) is required in two post-initiation pathways for transcription in the C. elegans embryo. Genes Dev 16(16):2135–2146. https://doi.org/10.1101/gad.999002 CrossRefPubMedPubMedCentral

Titel: Inhibition of cyclin-dependent kinases by AT7519 enhances nasopharyngeal carcinoma cell response to chemotherapy
verfasst von: Xin Wei
Jiabin Nian
Jing Zheng
Yangli He
Min Zeng
Publikationsdatum: 11.04.2020
Verlag: Springer Berlin Heidelberg
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 5/2020
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-020-04068-2

Die Highlights vom Kongress des American College of Cardiology 2024

Springer Medizin

Inhibition of cyclin-dependent kinases by AT7519 enhances nasopharyngeal carcinoma cell response to chemotherapy

Abstract

Background

Materials and methods

Results

Conclusions

Neu im Fachgebiet Onkologie

Alphablocker schützt vor Miktionsproblemen nach der Biopsie

Antikörper-Wirkstoff-Konjugat hält solide Tumoren in Schach

Mammakarzinom: Senken Statine das krebsbedingte Sterberisiko?

Labor, CT-Anthropometrie zeigen Risiko für Pankreaskrebs

Update Onkologie

Die Highlights vom Kongress des American College of Cardiology 2024

Springer Medizin

Abstract

Background

Materials and methods

Results

Conclusions

Bitte loggen Sie sich ein, um Zugang zu diesem Inhalt zu erhalten

Weitere Artikel der Ausgabe 5/2020

Pharmacokinetics of polatuzumab vedotin in combination with R/G-CHP in patients with B-cell non-Hodgkin lymphoma

The influence of PD-L1 genetic variation on the prognosis of R0 resection colorectal cancer patients received capecitabine-based adjuvant chemotherapy: a long-term follow-up, real-world retrospective study

Cerebrospinal fluid penetration of the colony-stimulating factor-1 receptor (CSF-1R) inhibitor, pexidartinib

Intravenous 5-fluoro-2′-deoxycytidine administered with tetrahydrouridine increases the proportion of p16-expressing circulating tumor cells in patients with advanced solid tumors

Phase 1 study of napabucasin, a cancer stemness inhibitor, in patients with advanced solid tumors

Phase I study of lapatinib plus trametinib in patients with KRAS-mutant colorectal, non-small cell lung, and pancreatic cancer

Neu im Fachgebiet Onkologie

Alphablocker schützt vor Miktionsproblemen nach der Biopsie

Antikörper-Wirkstoff-Konjugat hält solide Tumoren in Schach

Mammakarzinom: Senken Statine das krebsbedingte Sterberisiko?

Labor, CT-Anthropometrie zeigen Risiko für Pankreaskrebs

Update Onkologie