The undruggable nature of oncogenic Myc transcription factors poses a therapeutic challenge in neuroblastoma, a pediatric cancer in which MYCN amplification is strongly associated with unfavorable outcome. Here, we show that CYC065 (fadraciclib), a clinical inhibitor of CDK9 and CDK2, selectively targeted MYCN-amplified neuroblastoma via multiple mechanisms. CDK9 — a component of the transcription elongation complex P-TEFb — bound to the MYCN-amplicon superenhancer, and its inhibition resulted in selective loss of nascent MYCN transcription. MYCN loss led to growth arrest, sensitizing cells for apoptosis following CDK2 inhibition. In MYCN-amplified neuroblastoma, MYCN invaded active enhancers, driving a transcriptionally encoded adrenergic gene expression program that was selectively reversed by CYC065. MYCN overexpression in mesenchymal neuroblastoma was sufficient to induce adrenergic identity and sensitize cells to CYC065. CYC065, used together with temozolomide, a reference therapy for relapsed neuroblastoma, caused long-term suppression of neuroblastoma growth in vivo, highlighting the clinical potential of CDK9/2 inhibition in the treatment of MYCN-amplified neuroblastoma.
Evon Poon, Tong Liang, Yann Jamin, Susanne Walz, Colin Kwok, Anne Hakkert, Karen Barker, Zuzanna Urban, Khin Thway, Rhamy Zeid, Albert Hallsworth, Gary Box, Marli E. Ebus, Marco P. Licciardello, Yordan Sbirkov, Glori Lazaro, Elizabeth Calton, Barbara M. Costa, Melanie Valenti, Alexis De Haven Brandon, Hannah Webber, Nicolas Tardif, Gilberto S. Almeida, Rossitza Christova, Gunther Boysen, Mark W. Richards, Giuseppe Barone, Anthony Ford, Richard Bayliss, Paul A. Clarke, Johann De Bono, Nathanael S. Gray, Julian Blagg, Simon P. Robinson, Suzanne A. Eccles, Daniella Zheleva, James E. Bradner, Jan Molenaar, Igor Vivanco, Martin Eilers, Paul Workman, Charles Y. Lin, Louis Chesler
Title and authors | Publication | Year |
---|---|---|
T cells in the microenvironment of solid pediatric tumors: the case of neuroblastoma
Maggi E, Landolina N, Munari E, Mariotti FR, Tumino N, Vacca P, Azzarone B, Moretta L |
Frontiers in Immunology | 2025 |
ATRX mutations mediate an immunogenic phenotype and macrophage infiltration in neuroblastoma
Lorenzi F, Jostes S, Gao Q, Hutchinson JC, Tall J, Martins da Costa B, Cooke AJ, Rampling D, Ogunbiyi O, Barker K, Hughes D, Barone G, Barisa M, Bellini A, Hubank M, Schleiermacher G, Anderson J, Bernstein E, Chesler L, George SL |
Cancer letters | 2025 |
Response of GEM models of neuroblastoma to cabozantinib assessed by multiparametric magnetic resonance imaging
Almeida GS, King P, Hallsworth A, Webber H, Popov S, Miranda S, Yogev O, Pearson AD, Chesler L, Jamin Y, Robinson SP |
Neoplasia (New York, N.Y.) | 2025 |
The MYCN 5′ UTR as a therapeutic target in neuroblastoma
Volegova MP, Brown LE, Banerjee U, Dries R, Sharma B, Kennedy A, Porco JA Jr, George RE |
Cell Reports | 2024 |
Advances in Cancer Therapy: A Comprehensive Review of CDK and EGFR Inhibitors
Hawash M |
Cells | 2024 |
CDK9 inhibitors for the treatment of solid tumors.
Mo C, Wei N, Li T, Ahmed Bhat M, Mohammadi M, Kuang C, Mo C, Wei N, Li T, Ahmed Bhat M, Mohammadi M, Kuang C |
Biochemical pharmacology | 2024 |
Targeting CDK2 to combat drug resistance in cancer therapy
Kasirzadeh S, Lenjisa JL, Wang S |
Future Oncology | 2024 |
Wilms tumor primary cultures capture phenotypic heterogeneity and facilitate preclinical screening
Götz L, Wegert J, Paikari A, Appenzeller S, Bausenwein S, Vokuhl C, Treger TD, Drost J, Linderkamp C, Schneider DT, Ernestus K, Warman SW, Fuchs J, Welter N, Graf N, Behjati S, Furtwängler R, Gessler M |
Translational Oncology | 2024 |
Antagonistic effect of cyclin-dependent kinases and a calcium-dependent phosphatase on polyglutamine-expanded androgen receptor toxic gain of function
Piol D, Tosatto L, Zuccaro E, Anderson EN, Falconieri A, Polanco MJ, Marchioretti C, Lia F, White J, Bregolin E, Minervini G, Parodi S, Salvatella X, Arrigoni G, Ballabio A, La Spada AR, Tosatto SC, Sambataro F, Medina DL, Pandey UB, Basso M, Pennuto M |
Science Advances | 2023 |
A Review of the Regulatory Mechanisms of N-Myc on Cell Cycle
Li HL, Dong LL, Jin MJ, Li QY, Wang X, Jia MQ, Song J, Zhang SY, Yuan S |
Molecules (Basel, Switzerland) | 2023 |
Drugging Hijacked Kinase Pathways in Pediatric Oncology: Opportunities and Current Scenario
Candido MF, Medeiros M, Veronez LC, Bastos D, Oliveira KL, Pezuk JA, Valera ET, Brassesco MS |
Pharmaceutics | 2023 |
P-TEFb promotes cell survival upon p53 activation by suppressing intrinsic apoptosis pathway
Wang Z, Mačáková M, Bugai A, Kuznetsov SG, Hassinen A, Lenasi T, Potdar S, Friedel CC, Barborič M |
Nucleic Acids Research | 2023 |
The super elongation complex drives transcriptional addiction in MYCN-amplified neuroblastoma
Wang D, Yin Z, Wang H, Wang L, Li T, Xiao R, Xie T, Han R, Dong R, Liu H, Liang K, Qing G |
Science Advances | 2023 |
Targeting CDK9 with selective inhibitors or degraders in tumor therapy: an overview of recent developments
Xiao L, Liu Y, Chen H, Shen L |
Cancer biology & therapy | 2023 |
TAF1D promotes proliferation by transcriptionally activating G2/M phase-related genes in MYCN-amplified neuroblastoma.
Zhang X, Zhan S, Guan X, Zhang Y, Lu J, Yu Y, Jin Y, Yang Y, Chu P, Hong E, Yang H, Ren H, Geng D, Wang Y, Zhou P, Guo Y, Chang Y |
Cancer Science | 2023 |
Targeting Myc-driven stress addiction in colorectal cancer
Saeed H, Leibowitz BJ, Zhang L, Yu J |
Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy | 2023 |
Targeting Transcriptional Regulation with a CDK9 Inhibitor Suppresses Growth of Endocrine- and Palbociclib-Resistant ER+ Breast Cancers
Soosainathan A, Iravani M, El-Botty R, Alexander J, Sourd L, Morisset L, Painsec P, Orha R, Nikitorowicz-Buniak J, Pancholi S, Haider S, Dowsett M, Marangoni E, Martin LA, Isacke CM |
Cancer research | 2023 |
Indisulam targets RNA splicing and metabolism to serve as a therapeutic strategy for high-risk neuroblastoma
A Nijhuis, A Sikka, O Yogev, L Herendi, C Balcells, Y Ma, E Poon, C Eckold, G Valbuena, Y Xu, Y Liu, B da Costa, M Gruet, C Wickremesinghe, A Benito, H Kramer, A Montoya, D Carling, E Want, Y Jamin, L Chesler, H Keun |
Nature Communications | 2022 |
Cyclin-dependent kinase inhibitor fadraciclib (CYC065) depletes anti-apoptotic protein and synergizes with venetoclax in primary chronic lymphocytic leukemia cells
R Chen, Y Chen, P Xiong, D Zheleva, D Blake, M Keating, W Wierda, W Plunkett |
Leukemia | 2022 |
Synthetic lethality of cyclin-dependent kinase inhibitor Dinaciclib with VHL -deficiency allows for selective targeting of clear cell renal cell carcinoma
L Nelson, K Castro, B Xu, J Li, N Dinh, J Thompson, J Woytash, K Kipp, O Razorenova |
Cell cycle (Georgetown, Tex.) | 2022 |
TP53 and TP53-associated genes are correlated with the prognosis of paediatric neuroblastoma
H Wang, X Wang, L Xu, J Zhang |
2022 | |
Intrinsic transcriptional heterogeneity in neuroblastoma guides mechanistic and therapeutic insights
Shendy NA, Zimmerman MW, Abraham BJ, Durbin AD |
Cell reports. Medicine | 2022 |
CDK9 inhibitors in cancer research
Huang Z, Wang T, Wang C, Fan Y |
2022 | |
Selective CDK9 Inhibition by Natural Compound Toyocamycin in Cancer Cells
Pandey S, Djibo R, Darracq A, Calendo G, Zhang H, Henry RA, Andrews AJ, Baylin SB, Madzo J, Najmanovich R, Issa JP, Raynal NJ |
Cancers | 2022 |
Immunotherapy of Neuroblastoma: Facts and Hopes
Anderson J, Majzner RG, Sondel PM |
Clinical cancer research | 2022 |
Targeting the Heterogeneous Genomic Landscape in Triple-Negative Breast Cancer through Inhibitors of the Transcriptional Machinery
van der Noord VE, van de Water B, Le Dévédec SE |
Cancers | 2022 |
IGF2BP3 is an essential N6-methyladenosine biotarget for suppressing ferroptosis in lung adenocarcinoma cells
Xu X, Cui J, Wang H, Ma L, Zhang X, Guo W, Xue X, Wang Y, Qiu S, Tian X, Miao Y, Wu M, Yu Y, Xu Y, Wang J, Qiao Y |
2022 | |
The BRD4 Inhibitor dBET57 Exerts Anticancer Effects by Targeting Superenhancer-Related Genes in Neuroblastoma.
Jia SQ, Zhuo R, Zhang ZM, Yang Y, Tao YF, Wang JW, Li XL, Xie Y, Li G, Wu D, Chen YL, Yu JJ, Feng CX, Li ZH, Zhou RF, Yang RD, Yang PC, Zhou B, Wan XM, Wu YM, Jiao WY, Zhou NN, Fang F, Pan J |
Journal of Immunology Research | 2022 |
Remarkable Synergy When Combining EZH2 Inhibitors with YM155 Is H3K27me3-Independent
Yang J, Davidoff AM |
Cancers | 2022 |
Targeting cyclin-dependent kinase 9 in cancer therapy
Y Shen, Y Wang, Y Zhang, S Ma, L Yang, C Zhao, X Huang |
Acta Pharmacologica Sinica | 2021 |
Targeting MYCN in Pediatric and Adult Cancers
Z Liu, SS Chen, S Clarke, V Veschi, CJ Thiele |
Frontiers in Oncology | 2021 |
Biological Role of MYCN in Medulloblastoma: Novel Therapeutic Opportunities and Challenges Ahead
S Shrestha, A Morcavallo, C Gorrini, L Chesler |
Frontiers in Oncology | 2021 |
Targeting Oncogenic Transcriptional Networks in Neuroblastoma: From N-Myc to Epigenetic Drugs
R Ciaccio, PD Rosa, S Aloisi, M Viggiano, L Cimadom, SK Zadran, G Perini, G Milazzo |
International journal of molecular sciences | 2021 |
Targeting Myc Interacting Proteins as a Winding Path in Cancer Therapy
Y Zhou, X Gao, M Yuan, B Yang, Q He, J Cao |
Frontiers in pharmacology | 2021 |
Molecular Mechanisms of MYCN Dysregulation in Cancers
R Liu, P Shi, Z Wang, C Yuan, H Cui |
Frontiers in Oncology | 2021 |
Identification of CDK2-Related Immune Forecast Model and ceRNA in Lung Adenocarcinoma, a Pan-Cancer Analysis
TT Liu, R Li, C Huo, JP Li, J Yao, X Ji, YQ Qu |
Frontiers in Cell and Developmental Biology | 2021 |
Cyclin-dependent kinase (CDK) inhibitors in solid tumors: a review of clinical trials
E Panagiotou, G Gomatou, IP Trontzas, N Syrigos, E Kotteas |
Clinical and Translational Oncology | 2021 |
Transcriptional CDK inhibitors, CYC065 and THZ1 promote Bim-dependent apoptosis in primary and recurrent GBM through cell cycle arrest and Mcl-1 downregulation
V Juric, L Hudson, J Fay, CE Richards, H Jahns, M Verreault, F Bielle, A Idbaih, ML Lamfers, AM Hopkins, M Rehm, BM Murphy |
Cell Death and Disease | 2021 |
The biguanide polyamine analog verlindamycin promotes differentiation in neuroblastoma via induction of antizyme
Urban-Wójciuk Z, Graham A, Barker K, Kwok C, Sbirkov Y, Howell L, Campbell J, Woster PM, Poon E, Petrie K, Chesler L |
Cancer Gene Therapy | 2021 |
Pulmonary surfactant: an immunological perspective
ZC Chroneos, Z Sever-Chroneos, VL Shepherd |
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology | 2009 |