Cell death & disease, 2024-05, Vol.15 (5), p.345-345, Article 345
2024
Details
- Autor(en) / Beteiligte
- Titel
- CDK9 inhibition as an effective therapy for small cell lung cancer
- Ist Teil von
- Cell death & disease, 2024-05, Vol.15 (5), p.345-345, Article 345
- Ort / Verlag
- England: Springer Nature B.V
- Erscheinungsjahr
- 2024
- Link zum Volltext
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2041-4889eISSN: 2041-4889DOI: 10.1038/s41419-024-06724-4Titel-ID: cdi_doaj_primary_oai_doaj_org_article_a58ced927e1244248717a2ab04025c86
- Format
- –
- Schlagworte
- Animals, Apoptosis, Apoptosis - drug effects, Bridged Bicyclo Compounds, Heterocyclic - pharmacology, Bridged Bicyclo Compounds, Heterocyclic - therapeutic use, c-FLIP protein, Cancer therapies, Cell Line, Tumor, Chemotherapy, Cisplatin, Cyclic N-Oxides - pharmacology, Cyclin-dependent kinase, Cyclin-Dependent Kinase 9 - antagonists & inhibitors, Cyclin-Dependent Kinase 9 - metabolism, Cyclin-dependent kinases, Etoposide, Humans, Indolizines - pharmacology, Kinases, Lung cancer, Lung Neoplasms - drug therapy, Lung Neoplasms - pathology, Mcl-1 protein, Mice, PD-L1 protein, Protein Kinase Inhibitors - pharmacology, Protein Kinase Inhibitors - therapeutic use, Pyridinium Compounds - pharmacology, Pyridinium Compounds - therapeutic use, Small cell lung carcinoma, Small Cell Lung Carcinoma - drug therapy, Small Cell Lung Carcinoma - pathology, Tumors