2. Academic Validation
  3. Degradation of CCNK/CDK12 is a druggable vulnerability of colorectal cancer

Degradation of CCNK/CDK12 is a druggable vulnerability of colorectal cancer

  • Cell Rep. 2021 Jul 20;36(3):109394. doi: 10.1016/j.celrep.2021.109394.
Sebastian M Dieter 1,  Christine Siegl 2,  Paula L Codó 3,  Mario Huerta 4,  Anna L Ostermann-Parucha 4,  Erik Schulz 5,  Martina K Zowada 6,  Sylvia Martin 4,  Karin Laaber 6,  Ali Nowrouzi 7,  Mona Blatter 8,  Sina Kreth 8,  Frank Westermann 8,  Axel Benner 9,  Ulrike Uhrig 10,  Kerstin Putzker 10,  Joe Lewis 10,  Andrea Haegebarth 11,  Dominik Mumberg 11,  Simon J Holton 12,  Joerg Weiske 12,  Lena-Marit Toepper 12,  Ulrike Scheib 12,  Gerhard Siemeister 12,  Claudia R Ball 13,  Bernhard Kuster 14,  Gabriele Stoehr 15,  Hannes Hahne 15,  Sarah Johannes 16,  Martin Lange 12,  Friederike Herbst 4,  Hanno Glimm 17
Affiliations

Affiliations

  • 1 Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ), 01307 Dresden, Germany; Translational Functional Cancer Genomics, NCT and DKFZ Heidelberg, 69120 Heidelberg, Germany. Electronic address: [email protected].
  • 2 Merck KGaA, 64293 Darmstadt, Germany.
  • 3 Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ), 01307 Dresden, Germany; Translational Functional Cancer Genomics, NCT and DKFZ Heidelberg, 69120 Heidelberg, Germany; CureVac AG, 60325 Frankfurt am Main, Germany.
  • 4 Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ), 01307 Dresden, Germany; Translational Functional Cancer Genomics, NCT and DKFZ Heidelberg, 69120 Heidelberg, Germany.
  • 5 Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, 69120 Heidelberg, Germany.
  • 6 Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ), 01307 Dresden, Germany; Translational Functional Cancer Genomics, NCT and DKFZ Heidelberg, 69120 Heidelberg, Germany; Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany.
  • 7 Division of Molecular and Translational Radiation Oncology, Heidelberg Medical Faculty, Heidelberg University, 69120 Heidelberg, Germany.
  • 8 Hopp Children's Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, Germany; Division of Neuroblastoma Genomics, DKFZ Heidelberg, 69120 Heidelberg, Germany.
  • 9 Division of Biostatistics, DKFZ Heidelberg, 69120 Heidelberg, Germany.
  • 10 European Molecular Biology Laboratory (EMBL), Chemical Biology Core Facility, 69117 Heidelberg, Germany.
  • 11 Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany.
  • 12 Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany; Nuvisan Innovation Campus Berlin GmbH, 13353 Berlin, Germany.
  • 13 Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ), 01307 Dresden, Germany; Translational Functional Cancer Genomics, NCT and DKFZ Heidelberg, 69120 Heidelberg, Germany; German Cancer Consortium (DKTK), 01307 Dresden, Germany; Center for Personalized Oncology, University Hospital Carl Gustav Carus Dresden at TU Dresden, 01307 Dresden, Germany.
  • 14 Chair of Proteomics and Bioanalytics, Technical University of Munich, 85354 Freising, Germany.
  • 15 OmicScouts GmbH, 85354 Freising, Germany.
  • 16 Bayer AG, Research & Development, Pharmaceuticals, 42117 Wuppertal, Germany.
  • 17 Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ), 01307 Dresden, Germany; Translational Functional Cancer Genomics, NCT and DKFZ Heidelberg, 69120 Heidelberg, Germany; German Cancer Consortium (DKTK), 01307 Dresden, Germany; Center for Personalized Oncology, University Hospital Carl Gustav Carus Dresden at TU Dresden, 01307 Dresden, Germany. Electronic address: [email protected].
PMID: 34289372 DOI: 10.1016/j.celrep.2021.109394
Abstract

Novel treatment options for metastatic colorectal Cancer (CRC) are urgently needed to improve patient outcome. Here, we screen a library of non-characterized small molecules against a heterogeneous collection of patient-derived CRC spheroids. By prioritizing compounds with inhibitory activity in a subset of-but not all-spheroid cultures, NCT02 is identified as a candidate with minimal risk of non-specific toxicity. Mechanistically, we show that NCT02 acts as molecular glue that induces ubiquitination of cyclin K (CCNK) and proteasomal degradation of CCNK and its complex partner CDK12. Knockout of CCNK or CDK12 decreases proliferation of CRC cells in vitro and tumor growth in vivo. Interestingly, sensitivity to pharmacological CCNK/CDK12 degradation is associated with TP53 deficiency and consensus molecular subtype 4 in vitro and in patient-derived xenografts. We thus demonstrate the efficacy of targeted CCNK/CDK12 degradation for a CRC subset, highlighting the potential of drug-induced proteolysis for difficult-to-treat types of Cancer.

Keywords

CCNK; CDK12; colorectal cancer; molecular glue degrader; targeted protein degradation.

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