CDK9 inhibition as an effective therapy for small cell lung cancer

L Valdez Capuccino; T Kleitke; B Szokol; L Svajda; F Martin; F Bonechi; M Krekó; S Azami; A Montinaro; Y Wang; V Nikolov; L Kaiser; D Bonasera; J Saggau; T Scholz; A Schmitt; F Beleggia; H C Reinhardt; J George; G Liccardi; H Walczak; J Tóvári; J Brägelmann; J Montero; M L Sos; L Őrfi; N Peltzer

doi:10.1038/s41419-024-06724-4

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.

Authors

L Valdez Capuccino^{1

2

3}, T Kleitke^{1

2

3}, B Szokol⁴, L Svajda⁵, F Martin^{6

7

8}, F Bonechi^{1

2

3}, M Krekó^{4

9}, S Azami^{1

2

3}, A Montinaro¹⁰, Y Wang^{1

2

3}, V Nikolov^{3

11}, L Kaiser¹, D Bonasera^{2

11

12}, J Saggau^{2

11

12}, T Scholz^{1

2}, A Schmitt¹³, F Beleggia^{1

13

14}, H C Reinhardt¹⁵, J George^{1

16}, G Liccardi^{2

12}, H Walczak^{3

10

11}, J Tóvári⁵, 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.

MeSH terms

Animals
Apoptosis / drug effects
Bridged Bicyclo Compounds, Heterocyclic / pharmacology
Bridged Bicyclo Compounds, Heterocyclic / therapeutic use
Cell Line, Tumor
Cyclic N-Oxides / pharmacology
Cyclin-Dependent Kinase 9* / antagonists & inhibitors
Cyclin-Dependent Kinase 9* / metabolism
Humans
Indolizines* / pharmacology
Lung Neoplasms* / drug therapy
Lung Neoplasms* / pathology
Mice
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use
Pyridinium Compounds* / pharmacology
Pyridinium Compounds* / therapeutic use
Small Cell Lung Carcinoma* / drug therapy
Small Cell Lung Carcinoma* / pathology

Substances

CDK9 protein, human
dinaciclib

Abstract

MeSH terms

Substances

Grants and funding