Journal Article

DKFZ-2024-01070

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png CDK9 inhibition as an effective therapy for small cell lung cancer.

Valdez Capuccino, L. ; Kleitke, T. ; Szokol, B. ; Svajda, L. ; Martin, F. ; Bonechi, F. ; Krekó, M. ; Azami, S. ; Montinaro, A. ; Wang, Y. ; Nikolov, V. ; Kaiser, L. ; Bonasera, D. ; Saggau, J. ; Scholz, T. ; Schmitt, A. ; Beleggia, F. ; Reinhardt, A.DKFZ* ; George, J. ; Liccardi, G. ; Walczak, H. ; Tóvári, J. ; Brägelmann, J. ; Montero, J. ; Sos, M. L.DKFZ* ; Őrfi, L. ; Peltzer, N.

2024
Nature Publishing Group London [u.a.]

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Please use a persistent id in citations: doi:10.1038/s41419-024-06724-4

Abstract: Treatment-naïve small cell lung cancer (SCLC) is typically susceptible to standard-of-care chemotherapy consisting of cisplatin and etoposide recently combined with PD-L1 inhibitors. Yet, in most cases, SCLC patients develop resistance to first-line therapy and alternative therapies are urgently required to overcome this resistance. In this study, we tested the efficacy of dinaciclib, an FDA-orphan drug and inhibitor of the cyclin-dependent kinase (CDK) 9, among other CDKs, in SCLC. Furthermore, we report on a newly developed, highly specific CDK9 inhibitor, VC-1, with tumour-killing activity in SCLC. CDK9 inhibition displayed high killing potential in a panel of mouse and human SCLC cell lines. Mechanistically, CDK9 inhibition led to a reduction in MCL-1 and cFLIP anti-apoptotic proteins and killed cells, almost exclusively, by intrinsic apoptosis. While CDK9 inhibition did not synergise with chemotherapy, it displayed high efficacy in chemotherapy-resistant cells. In vivo, CDK9 inhibition effectively reduced tumour growth and improved survival in both autochthonous and syngeneic SCLC models. Together, this study shows that CDK9 inhibition is a promising therapeutic agent against SCLC and could be applied to chemo-refractory or resistant SCLC.

Keyword(s): Cyclin-Dependent Kinase 9: antagonists & inhibitors (MeSH) ; Cyclin-Dependent Kinase 9: metabolism (MeSH) ; Small Cell Lung Carcinoma: drug therapy (MeSH) ; Small Cell Lung Carcinoma: pathology (MeSH) ; Humans (MeSH) ; Animals (MeSH) ; Lung Neoplasms: drug therapy (MeSH) ; Lung Neoplasms: pathology (MeSH) ; Cell Line, Tumor (MeSH) ; Mice (MeSH) ; Pyridinium Compounds: pharmacology (MeSH) ; Pyridinium Compounds: therapeutic use (MeSH) ; Indolizines: pharmacology (MeSH) ; Cyclic N-Oxides: pharmacology (MeSH) ; Apoptosis: drug effects (MeSH) ; Bridged Bicyclo Compounds, Heterocyclic: pharmacology (MeSH) ; Bridged Bicyclo Compounds, Heterocyclic: therapeutic use (MeSH) ; Protein Kinase Inhibitors: pharmacology (MeSH) ; Protein Kinase Inhibitors: therapeutic use (MeSH) ; CDK9 protein, human ; dinaciclib

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Contributing Institute(s):

1. DKTK Koordinierungsstelle Essen/Düsseldorf (ED01)
2. DKTK Koordinierungsstelle München (MU01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2024

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