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024 7 _ |a 10.1038/s41419-024-06724-4
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082 _ _ |a 570
100 1 _ |a Valdez Capuccino, L.
|b 0
245 _ _ |a CDK9 inhibition as an effective therapy for small cell lung cancer.
260 _ _ |a London [u.a.]
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|b Nature Publishing Group
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520 _ _ |a 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.
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650 _ 7 |a CDK9 protein, human
|2 NLM Chemicals
650 _ 7 |a dinaciclib
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650 _ 2 |a Cyclin-Dependent Kinase 9: antagonists & inhibitors
|2 MeSH
650 _ 2 |a Cyclin-Dependent Kinase 9: metabolism
|2 MeSH
650 _ 2 |a Small Cell Lung Carcinoma: drug therapy
|2 MeSH
650 _ 2 |a Small Cell Lung Carcinoma: pathology
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Lung Neoplasms: drug therapy
|2 MeSH
650 _ 2 |a Lung Neoplasms: pathology
|2 MeSH
650 _ 2 |a Cell Line, Tumor
|2 MeSH
650 _ 2 |a Mice
|2 MeSH
650 _ 2 |a Pyridinium Compounds: pharmacology
|2 MeSH
650 _ 2 |a Pyridinium Compounds: therapeutic use
|2 MeSH
650 _ 2 |a Indolizines: pharmacology
|2 MeSH
650 _ 2 |a Cyclic N-Oxides: pharmacology
|2 MeSH
650 _ 2 |a Apoptosis: drug effects
|2 MeSH
650 _ 2 |a Bridged Bicyclo Compounds, Heterocyclic: pharmacology
|2 MeSH
650 _ 2 |a Bridged Bicyclo Compounds, Heterocyclic: therapeutic use
|2 MeSH
650 _ 2 |a Protein Kinase Inhibitors: pharmacology
|2 MeSH
650 _ 2 |a Protein Kinase Inhibitors: therapeutic use
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700 1 _ |a Kleitke, T.
|0 0009-0007-6288-7216
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700 1 _ |a Szokol, B.
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700 1 _ |a Svajda, L.
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700 1 _ |a Martin, F.
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700 1 _ |a Bonechi, F.
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700 1 _ |a Krekó, M.
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700 1 _ |a Azami, S.
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700 1 _ |a Montinaro, A.
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700 1 _ |a Wang, Y.
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700 1 _ |a Nikolov, V.
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700 1 _ |a Kaiser, L.
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700 1 _ |a Bonasera, D.
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700 1 _ |a Saggau, J.
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700 1 _ |a Scholz, T.
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700 1 _ |a Schmitt, A.
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700 1 _ |a Beleggia, F.
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700 1 _ |a Reinhardt, Annekathrin
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700 1 _ |a George, J.
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700 1 _ |a Liccardi, G.
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700 1 _ |a Walczak, H.
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700 1 _ |a Tóvári, J.
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700 1 _ |a Brägelmann, J.
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700 1 _ |a Montero, J.
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700 1 _ |a Sos, M. L.
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700 1 _ |a Őrfi, L.
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700 1 _ |a Peltzer, N.
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773 _ _ |a 10.1038/s41419-024-06724-4
|g Vol. 15, no. 5, p. 345
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