Universität zu Köln

Valdez Capuccino, L., Kleitke, T. ORCID: 0009-0007-6288-7216, Szokol, B., Svajda, L., Martin, F. ORCID: 0000-0002-3496-9093, Bonechi, F., Krekó, M., Azami, S. ORCID: 0000-0002-8702-6881, Montinaro, A. ORCID: 0000-0002-2289-9374, Wang, Y., Nikolov, V., Kaiser, L. ORCID: 0000-0002-3212-576X, Bonasera, D. ORCID: 0000-0003-1567-2283, Saggau, J. ORCID: 0000-0002-9908-5467, Scholz, T. ORCID: 0009-0002-4677-4178, Schmitt, A. ORCID: 0009-0002-7655-1805, Beleggia, F. ORCID: 0000-0003-0234-7094, Reinhardt, H. C., George, J., Liccardi, G. ORCID: 0000-0002-2662-1281, Walczak, H. ORCID: 0000-0002-6312-4591, Tóvári, J., Brägelmann, J. ORCID: 0000-0002-1306-2169, Montero, J., Sos, M. L. ORCID: 0000-0002-2868-100X, Őrfi, L. and Peltzer, N. ORCID: 0000-0002-4134-5852 (2024). CDK9 inhibition as an effective therapy for small cell lung cancer. Cell Death & Disease, 15 (5). pp. 1-12. Springer Nature. ISSN 2041-4889

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Abstract

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.

Item Type:	Article
Creators:	Creators Email ORCID ORCID Put Code Valdez Capuccino, L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kleitke, T. UNSPECIFIED https://orcid.org/0009-0007-6288-7216 UNSPECIFIED Szokol, B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Svajda, L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Martin, F. UNSPECIFIED https://orcid.org/0000-0002-3496-9093 UNSPECIFIED Bonechi, F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Krekó, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Azami, S. UNSPECIFIED https://orcid.org/0000-0002-8702-6881 UNSPECIFIED Montinaro, A. UNSPECIFIED https://orcid.org/0000-0002-2289-9374 UNSPECIFIED Wang, Y. UNSPECIFIED UNSPECIFIED UNSPECIFIED Nikolov, V. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kaiser, L. UNSPECIFIED https://orcid.org/0000-0002-3212-576X UNSPECIFIED Bonasera, D. UNSPECIFIED https://orcid.org/0000-0003-1567-2283 UNSPECIFIED Saggau, J. UNSPECIFIED https://orcid.org/0000-0002-9908-5467 UNSPECIFIED Scholz, T. UNSPECIFIED https://orcid.org/0009-0002-4677-4178 UNSPECIFIED Schmitt, A. UNSPECIFIED https://orcid.org/0009-0002-7655-1805 UNSPECIFIED Beleggia, F. UNSPECIFIED https://orcid.org/0000-0003-0234-7094 UNSPECIFIED Reinhardt, H. C. UNSPECIFIED UNSPECIFIED UNSPECIFIED George, J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Liccardi, G. UNSPECIFIED https://orcid.org/0000-0002-2662-1281 UNSPECIFIED Walczak, H. UNSPECIFIED https://orcid.org/0000-0002-6312-4591 UNSPECIFIED Tóvári, J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Brägelmann, J. UNSPECIFIED https://orcid.org/0000-0002-1306-2169 UNSPECIFIED Montero, J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sos, M. L. UNSPECIFIED https://orcid.org/0000-0002-2868-100X UNSPECIFIED Őrfi, L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Peltzer, N. UNSPECIFIED https://orcid.org/0000-0002-4134-5852 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-815562
Identification Number:	10.1038/s41419-024-06724-4
Journal or Publication Title:	Cell Death & Disease
Volume:	15
Number:	5
Page Range:	pp. 1-12
Number of Pages:	12
Date:	20 May 2024
Publisher:	Springer Nature
ISSN:	2041-4889
Language:	English
Faculty:	Faculty of Medicine
Divisions:	CECAD - Cluster of Excellence Cellular Stress Responses in Aging-Associated Diseases Faculty of Medicine > Biochemie > Institut I für Biochemie Faculty of Medicine > Hals-Nasen-Ohrenheilkunde > Klinik und Poliklinik für Hals-, Nasen- und Ohrenheilkunde Faculty of Medicine > Innere Medizin > Klinik I für Innere Medizin - Hämatologie und Onkologie Faculty of Medicine > Weitere > Translationale Genomik Zentrum für Molekulare Medizin
Subjects:	Life sciences Medical sciences Medicine
['eprint_fieldname_oa_funders' not defined]:	Publikationsfonds UzK
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/81556