%0 Journal Article
%A Valdez Capuccino, L.
%A Kleitke, T.
%A Szokol, B.
%A Svajda, L.
%A Martin, F.
%A Bonechi, F.
%A Krekó, M.
%A Azami, S.
%A Montinaro, A.
%A Wang, Y.
%A Nikolov, V.
%A Kaiser, L.
%A Bonasera, D.
%A Saggau, J.
%A Scholz, T.
%A Schmitt, A.
%A Beleggia, F.
%A Reinhardt, Annekathrin
%A George, J.
%A Liccardi, G.
%A Walczak, H.
%A Tóvári, J.
%A Brägelmann, J.
%A Montero, J.
%A Sos, M. L.
%A Őrfi, L.
%A Peltzer, N.
%T CDK9 inhibition as an effective therapy for small cell lung cancer.
%J Cell death & disease
%V 15
%N 5
%@ 2041-4889
%C London [u.a.]
%I Nature Publishing Group
%M DKFZ-2024-01070
%P 345
%D 2024
%X 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.
%K Cyclin-Dependent Kinase 9: antagonists & inhibitors
%K Cyclin-Dependent Kinase 9: metabolism
%K Small Cell Lung Carcinoma: drug therapy
%K Small Cell Lung Carcinoma: pathology
%K Humans
%K Animals
%K Lung Neoplasms: drug therapy
%K Lung Neoplasms: pathology
%K Cell Line, Tumor
%K Mice
%K Pyridinium Compounds: pharmacology
%K Pyridinium Compounds: therapeutic use
%K Indolizines: pharmacology
%K Cyclic N-Oxides: pharmacology
%K Apoptosis: drug effects
%K Bridged Bicyclo Compounds, Heterocyclic: pharmacology
%K Bridged Bicyclo Compounds, Heterocyclic: therapeutic use
%K Protein Kinase Inhibitors: pharmacology
%K Protein Kinase Inhibitors: therapeutic use
%K CDK9 protein, human (NLM Chemicals)
%K dinaciclib (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:38769311
%R 10.1038/s41419-024-06724-4
%U https://inrepo02.dkfz.de/record/290343