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  3. CDK9 inhibition as an effective therapy for small cell lung cancer

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

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. m.peltzer@uni-koeln.de.
  • 19 University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Molecular Medicine Cologne, Cologne, Germany. m.peltzer@uni-koeln.de.
  • 20 CECAD Research Center, University of Cologne, Cologne, Germany. m.peltzer@uni-koeln.de.
PMID: 38769311 DOI: 10.1038/s41419-024-06724-4
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.

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