CDK9 inhibition as an effective therapy for small cell lung cancer PMID: 38769311

ADC Targets in Oncology

2026-04-10

CDK9 inhibition as an effective therapy for small cell lung cancer

Cell Death Dis. 2024 May 20;15(5):345. doi: 10.1038/s41419-024-06724-4.

L Valdez Capuccino ¹ ² ³ , T Kleitke ¹ ² ³ , B Szokol ⁴ , L Svajda ⁵ , F Martin ⁶ ⁷ ⁸ , F Bonechi ¹ ² ³ , M Krekó ⁴ ⁹ , S Azami ¹ ² ³ , A Montinaro ¹⁰ , Y Wang ¹ ² ³ , V Nikolov ³ ¹¹ , L Kaiser ¹ , D Bonasera ² ¹¹ ¹² , J Saggau ² ¹¹ ¹² , T Scholz ¹ ² , A Schmitt ¹³ , F Beleggia ¹ ¹³ ¹⁴ , H C Reinhardt ¹⁵ , J George ¹ ¹⁶ , G Liccardi ² ¹² , H Walczak ³ ¹⁰ ¹¹ , J Tóvári ⁵ , J Brägelmann ¹ ² ¹⁴ , J Montero ⁶ ⁷ ⁸ , M L Sos ¹ ¹⁷ , L Őrfi ⁴ ⁹ , N Peltzer ¹⁸ ¹⁹ ²⁰

Affiliations

1. University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany.
2. University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Molecular Medicine Cologne, Cologne, Germany.
3. CECAD Research Center, University of Cologne, Cologne, Germany.
4. Vichem Chemie Research Ltd., Veszprém, Hungary.
5. Department of Experimental Pharmacology, and the National Tumor Biology Laboratory, National Institute of Oncology, Budapest, Hungary.
6. Institute for Bioengineering of Catalonia (IBEC), Barcelona Institute of Science and Technology (BIST), 08028, Barcelona, Spain.
7. Networking Biomedical Research Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 28029, Madrid, Spain.
8. Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, University of Barcelona, 08036, Barcelona, Spain.
9. Department of Pharmaceutical Chemistry, Semmelweis University, Budapest, Hungary.
10. Centre for Cell Death, Cancer, and Inflammation (CCCI), UCL Cancer Institute, University College London, London, UK.
11. Cell death, inflammation and immunity laboratory, Institute of Biochemistry I, Centre for Biochemistry, Faculty of Medicine, University of Cologne, Cologne, Germany.
12. Genome instability, inflammation and cell death laboratory, Institute of Biochemistry I, Centre for Biochemistry, Faculty of Medicine, University of Cologne, Cologne, Germany.
13. University Hospital of Cologne, Medical Faculty, Department I for Internal Medicine, Cologne, Germany.
14. University of Cologne, Faculty of Medicine and University Hospital Cologne, Mildred Scheel School of Oncology Cologne, Cologne, Germany.
15. Department of Hematology and Stem Cell Transplantation, University Hospital Essen, University Duisburg-Essen, German Cancer Consortium (DKTK partner site Essen), Essen, Germany.
16. Department of Otorhinolaryngology, Head and Neck Surgery, Faculty of Medicine and University Hospital Cologne, University Hospital of Cologne, Cologne, Germany.
17. Division for Translational Oncology, German Cancer Research Center (DKFZ), The German Consortium for Translational Cancer Research (DKTK), München Partner Site, Ludwig-Maximilian University München, Munich, Germany.
18. University of Cologne, Faculty of Medicine and University Hospital Cologne, Department of Translational Genomics, Cologne, Germany. [email protected].
19. University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Molecular Medicine Cologne, Cologne, Germany. [email protected].
20. CECAD Research Center, University of Cologne, Cologne, Germany. [email protected].

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.