Degradation of CCNK/CDK12 is a druggable vulnerability of colorectal cancer.
Antineoplastic Agents
/ chemistry
Apoptosis
/ drug effects
Cell Line, Tumor
Cell Proliferation
/ drug effects
Cell Self Renewal
/ drug effects
Colorectal Neoplasms
/ metabolism
Cyclin-Dependent Kinases
/ metabolism
Cyclins
/ metabolism
DNA Damage
Female
High-Throughput Screening Assays
Humans
Proteasome Endopeptidase Complex
/ metabolism
Proteolysis
/ drug effects
Proteomics
Spheroids, Cellular
/ drug effects
Tumor Suppressor Protein p53
/ metabolism
Ubiquitin-Protein Ligases
/ metabolism
Ubiquitination
/ drug effects
CCNK
CDK12
colorectal cancer
molecular glue degrader
targeted protein degradation
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
20 07 2021
20 07 2021
Historique:
received:
23
09
2020
revised:
08
04
2021
accepted:
23
06
2021
entrez:
21
7
2021
pubmed:
22
7
2021
medline:
9
2
2022
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34289372
pii: S2211-1247(21)00792-0
doi: 10.1016/j.celrep.2021.109394
pii:
doi:
Substances chimiques
Antineoplastic Agents
0
CCNK protein, human
0
Cyclins
0
Tumor Suppressor Protein p53
0
Ubiquitin-Protein Ligases
EC 2.3.2.27
CDK12 protein, human
EC 2.7.11.22
Cyclin-Dependent Kinases
EC 2.7.11.22
Proteasome Endopeptidase Complex
EC 3.4.25.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
109394Informations de copyright
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
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.