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

Sebastian M. Dieter; Christine Siegl; Paula L. Codó; Mario Huerta; Anna L. Ostermann-Parucha; Erik Schulz; Martina K. Zowada; Sylvia Martin; Karin Laaber; Ali Nowrouzi; Mona Blatter; Sina Kreth; Frank Westermann; Axel Benner; Ulrike Uhrig; Kerstin Putzker; Joe Lewis; Andrea Haegebarth; Dominik Mumberg; Simon J. Holton; Joerg Weiske; Lena Marit Toepper; Ulrike Scheib; Gerhard Siemeister; Claudia R. Ball; Bernhard Kuster; Gabriele Stoehr; Hannes Hahne; Sarah Johannes; Martin Lange; Friederike Herbst; Hanno Glimm

doi:10.1016/j.celrep.2021.109394

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

Sebastian M. Dieter, Christine Siegl, Paula L. Codó, Mario Huerta, Anna L. Ostermann-Parucha, Erik Schulz, Martina K. Zowada, Sylvia Martin, Karin Laaber, Ali Nowrouzi, Mona Blatter, Sina Kreth, Frank Westermann, Axel Benner, Ulrike Uhrig, Kerstin Putzker, Joe Lewis, Andrea Haegebarth, Dominik Mumberg, Simon J. HoltonJoerg Weiske, Lena Marit Toepper, Ulrike Scheib, Gerhard Siemeister, Claudia R. Ball, Bernhard Kuster, Gabriele Stoehr, Hannes Hahne, Sarah Johannes, Martin Lange, Friederike Herbst, Hanno Glimm

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Research output: Contribution to journal › Article › peer-review

45 Scopus citations

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.

Original language	English
Article number	109394
Journal	Cell Reports
Volume	36
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2021.109394
State	Published - 20 Jul 2021

Keywords

CCNK
CDK12
colorectal cancer
molecular glue degrader
targeted protein degradation

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2021.109394

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Dieter, S. M., Siegl, C., Codó, P. L., Huerta, M., Ostermann-Parucha, A. L., Schulz, E., Zowada, M. K., Martin, S., Laaber, K., Nowrouzi, A., Blatter, M., Kreth, S., Westermann, F., Benner, A., Uhrig, U., Putzker, K., Lewis, J., Haegebarth, A., Mumberg, D., ... Glimm, H. (2021). Degradation of CCNK/CDK12 is a druggable vulnerability of colorectal cancer. Cell Reports, 36(3), Article 109394. https://doi.org/10.1016/j.celrep.2021.109394

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title = "Degradation of CCNK/CDK12 is a druggable vulnerability of colorectal cancer",

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",

author = "Dieter, {Sebastian M.} and Christine Siegl and Cod{\'o}, {Paula L.} and Mario Huerta and Ostermann-Parucha, {Anna L.} and Erik Schulz and Zowada, {Martina K.} and Sylvia Martin and Karin Laaber and Ali Nowrouzi and Mona Blatter and Sina Kreth and Frank Westermann and Axel Benner and Ulrike Uhrig and Kerstin Putzker and Joe Lewis and Andrea Haegebarth and Dominik Mumberg and Holton, {Simon J.} and Joerg Weiske and Toepper, {Lena Marit} and Ulrike Scheib and Gerhard Siemeister and Ball, {Claudia R.} and Bernhard Kuster and Gabriele Stoehr and Hannes Hahne and Sarah Johannes and Martin Lange and Friederike Herbst and Hanno Glimm",

note = "Publisher Copyright: {\textcopyright} 2021 The Author(s)",

year = "2021",

month = jul,

day = "20",

doi = "10.1016/j.celrep.2021.109394",

language = "English",

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Dieter, SM, Siegl, C, Codó, PL, Huerta, M, Ostermann-Parucha, AL, Schulz, E, Zowada, MK, Martin, S, Laaber, K, Nowrouzi, A, Blatter, M, Kreth, S, Westermann, F, Benner, A, Uhrig, U, Putzker, K, Lewis, J, Haegebarth, A, Mumberg, D, Holton, SJ, Weiske, J, Toepper, LM, Scheib, U, Siemeister, G, Ball, CR, Kuster, B, Stoehr, G, Hahne, H, Johannes, S, Lange, M, Herbst, F & Glimm, H 2021, 'Degradation of CCNK/CDK12 is a druggable vulnerability of colorectal cancer', Cell Reports, vol. 36, no. 3, 109394. https://doi.org/10.1016/j.celrep.2021.109394

TY - JOUR

T1 - Degradation of CCNK/CDK12 is a druggable vulnerability of colorectal cancer

AU - Dieter, Sebastian M.

AU - Siegl, Christine

AU - Codó, Paula L.

AU - Huerta, Mario

AU - Ostermann-Parucha, Anna L.

AU - Schulz, Erik

AU - Zowada, Martina K.

AU - Martin, Sylvia

AU - Laaber, Karin

AU - Nowrouzi, Ali

AU - Blatter, Mona

AU - Kreth, Sina

AU - Westermann, Frank

AU - Benner, Axel

AU - Uhrig, Ulrike

AU - Putzker, Kerstin

AU - Lewis, Joe

AU - Haegebarth, Andrea

AU - Mumberg, Dominik

AU - Holton, Simon J.

AU - Weiske, Joerg

AU - Toepper, Lena Marit

AU - Scheib, Ulrike

AU - Siemeister, Gerhard

AU - Ball, Claudia R.

AU - Kuster, Bernhard

AU - Stoehr, Gabriele

AU - Hahne, Hannes

AU - Johannes, Sarah

AU - Lange, Martin

AU - Herbst, Friederike

AU - Glimm, Hanno

PY - 2021/7/20

Y1 - 2021/7/20

N2 - 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.

AB - 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.

KW - CCNK

KW - CDK12

KW - colorectal cancer

KW - molecular glue degrader

KW - targeted protein degradation

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U2 - 10.1016/j.celrep.2021.109394

DO - 10.1016/j.celrep.2021.109394

M3 - Article

C2 - 34289372

AN - SCOPUS:85110504442

SN - 2211-1247

VL - 36

JO - Cell Reports

JF - Cell Reports

IS - 3

M1 - 109394

ER -

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

Abstract

Keywords

UN SDGs

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