TY  - JOUR
AU  - Valdez Capuccino, L.
AU  - Kleitke, T.
AU  - Szokol, B.
AU  - Svajda, L.
AU  - Martin, F.
AU  - Bonechi, F.
AU  - Krekó, M.
AU  - Azami, S.
AU  - Montinaro, A.
AU  - Wang, Y.
AU  - Nikolov, V.
AU  - Kaiser, L.
AU  - Bonasera, D.
AU  - Saggau, J.
AU  - Scholz, T.
AU  - Schmitt, A.
AU  - Beleggia, F.
AU  - Reinhardt, Annekathrin
AU  - George, J.
AU  - Liccardi, G.
AU  - Walczak, H.
AU  - Tóvári, J.
AU  - Brägelmann, J.
AU  - Montero, J.
AU  - Sos, M. L.
AU  - Őrfi, L.
AU  - Peltzer, N.
TI  - CDK9 inhibition as an effective therapy for small cell lung cancer.
JO  - Cell death & disease
VL  - 15
IS  - 5
SN  - 2041-4889
CY  - London [u.a.]
PB  - Nature Publishing Group
M1  - DKFZ-2024-01070
SP  - 345
PY  - 2024
AB  - 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.
KW  - Cyclin-Dependent Kinase 9: antagonists & inhibitors
KW  - Cyclin-Dependent Kinase 9: metabolism
KW  - Small Cell Lung Carcinoma: drug therapy
KW  - Small Cell Lung Carcinoma: pathology
KW  - Humans
KW  - Animals
KW  - Lung Neoplasms: drug therapy
KW  - Lung Neoplasms: pathology
KW  - Cell Line, Tumor
KW  - Mice
KW  - Pyridinium Compounds: pharmacology
KW  - Pyridinium Compounds: therapeutic use
KW  - Indolizines: pharmacology
KW  - Cyclic N-Oxides: pharmacology
KW  - Apoptosis: drug effects
KW  - Bridged Bicyclo Compounds, Heterocyclic: pharmacology
KW  - Bridged Bicyclo Compounds, Heterocyclic: therapeutic use
KW  - Protein Kinase Inhibitors: pharmacology
KW  - Protein Kinase Inhibitors: therapeutic use
KW  - CDK9 protein, human (NLM Chemicals)
KW  - dinaciclib (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:38769311
DO  - DOI:10.1038/s41419-024-06724-4
UR  - https://inrepo02.dkfz.de/record/290343
ER  -