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. 2021 Jul 20;36(3):109394.
doi: 10.1016/j.celrep.2021.109394.

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

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
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Free article

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

Sebastian M Dieter et al. Cell Rep. .
Free article

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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Conflict of interest statement

Declaration of interests C.S. is an employee of Merck KGaA. P.L.C. is an employee of CureVac AG. A.N. is an employee of Spark Therapeutics Inc. A.H., D.M., S.J.H., U.S., J.W., L.-M.T., G.S., S.J., and M.L. are or were employees of Bayer AG and are shareholders or may have additional stock options. U.S., J.W., L.M.T., G. Stoehr, S.J.H., G. Siemeister, and M.L. are employees of Nuvisan ICB GmbH. G. Stoehr and H.H. are employees of OmicScouts GmbH. B.K. and H.H. are shareholders of OmicScouts GmbH. All other authors declare no competing interests.

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