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000290343 1001_ $$aValdez Capuccino, L.$$b0
000290343 245__ $$aCDK9 inhibition as an effective therapy for small cell lung cancer.
000290343 260__ $$aLondon [u.a.]$$bNature Publishing Group$$c2024
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000290343 520__ $$aTreatment-naïve small cell lung cancer (SCLC) is typically susceptible to standard-of-care chemotherapy consisting of cisplatin and etoposide recently combined with PD-L1 inhibitors. Yet, in most cases, SCLC patients develop resistance to first-line therapy and alternative therapies are urgently required to overcome this resistance. In this study, we tested the efficacy of dinaciclib, an FDA-orphan drug and inhibitor of the cyclin-dependent kinase (CDK) 9, among other CDKs, in SCLC. Furthermore, we report on a newly developed, highly specific CDK9 inhibitor, VC-1, with tumour-killing activity in SCLC. CDK9 inhibition displayed high killing potential in a panel of mouse and human SCLC cell lines. Mechanistically, CDK9 inhibition led to a reduction in MCL-1 and cFLIP anti-apoptotic proteins and killed cells, almost exclusively, by intrinsic apoptosis. While CDK9 inhibition did not synergise with chemotherapy, it displayed high efficacy in chemotherapy-resistant cells. In vivo, CDK9 inhibition effectively reduced tumour growth and improved survival in both autochthonous and syngeneic SCLC models. Together, this study shows that CDK9 inhibition is a promising therapeutic agent against SCLC and could be applied to chemo-refractory or resistant SCLC.
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000290343 650_7 $$2NLM Chemicals$$aCDK9 protein, human
000290343 650_7 $$2NLM Chemicals$$adinaciclib
000290343 650_2 $$2MeSH$$aCyclin-Dependent Kinase 9: antagonists & inhibitors
000290343 650_2 $$2MeSH$$aCyclin-Dependent Kinase 9: metabolism
000290343 650_2 $$2MeSH$$aSmall Cell Lung Carcinoma: drug therapy
000290343 650_2 $$2MeSH$$aSmall Cell Lung Carcinoma: pathology
000290343 650_2 $$2MeSH$$aHumans
000290343 650_2 $$2MeSH$$aAnimals
000290343 650_2 $$2MeSH$$aLung Neoplasms: drug therapy
000290343 650_2 $$2MeSH$$aLung Neoplasms: pathology
000290343 650_2 $$2MeSH$$aCell Line, Tumor
000290343 650_2 $$2MeSH$$aMice
000290343 650_2 $$2MeSH$$aPyridinium Compounds: pharmacology
000290343 650_2 $$2MeSH$$aPyridinium Compounds: therapeutic use
000290343 650_2 $$2MeSH$$aIndolizines: pharmacology
000290343 650_2 $$2MeSH$$aCyclic N-Oxides: pharmacology
000290343 650_2 $$2MeSH$$aApoptosis: drug effects
000290343 650_2 $$2MeSH$$aBridged Bicyclo Compounds, Heterocyclic: pharmacology
000290343 650_2 $$2MeSH$$aBridged Bicyclo Compounds, Heterocyclic: therapeutic use
000290343 650_2 $$2MeSH$$aProtein Kinase Inhibitors: pharmacology
000290343 650_2 $$2MeSH$$aProtein Kinase Inhibitors: therapeutic use
000290343 7001_ $$00009-0007-6288-7216$$aKleitke, T.$$b1
000290343 7001_ $$aSzokol, B.$$b2
000290343 7001_ $$aSvajda, L.$$b3
000290343 7001_ $$aMartin, F.$$b4
000290343 7001_ $$aBonechi, F.$$b5
000290343 7001_ $$aKrekó, M.$$b6
000290343 7001_ $$aAzami, S.$$b7
000290343 7001_ $$00000-0002-2289-9374$$aMontinaro, A.$$b8
000290343 7001_ $$aWang, Y.$$b9
000290343 7001_ $$aNikolov, V.$$b10
000290343 7001_ $$aKaiser, L.$$b11
000290343 7001_ $$aBonasera, D.$$b12
000290343 7001_ $$aSaggau, J.$$b13
000290343 7001_ $$aScholz, T.$$b14
000290343 7001_ $$aSchmitt, A.$$b15
000290343 7001_ $$00000-0003-0234-7094$$aBeleggia, F.$$b16
000290343 7001_ $$0P:(DE-He78)856d5c1d0205a79190ed88218ffaf9b2$$aReinhardt, Annekathrin$$b17
000290343 7001_ $$aGeorge, J.$$b18
000290343 7001_ $$00000-0002-2662-1281$$aLiccardi, G.$$b19
000290343 7001_ $$aWalczak, H.$$b20
000290343 7001_ $$aTóvári, J.$$b21
000290343 7001_ $$00000-0002-1306-2169$$aBrägelmann, J.$$b22
000290343 7001_ $$aMontero, J.$$b23
000290343 7001_ $$0P:(DE-He78)15fe7dad7c1f2bb1937fa3f998963b13$$aSos, M. L.$$b24$$udkfz
000290343 7001_ $$aŐrfi, L.$$b25
000290343 7001_ $$00000-0002-4134-5852$$aPeltzer, N.$$b26
000290343 773__ $$0PERI:(DE-600)2541626-1$$a10.1038/s41419-024-06724-4$$gVol. 15, no. 5, p. 345$$n5$$p345$$tCell death & disease$$v15$$x2041-4889$$y2024
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