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

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

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 invitro and tumor growth invivo. Interestingly, sensitivity to pharmacological CCNK/CDK12 degradation is associated with TP53 deficiency and consensus molecular subtype 4 invitro 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.

Highlights

The response of a malignant tumor to drug treatment can be significantly mitigated by cellular heterogeneity (Dagogo-Jack and Shaw, 2018)
A collection of primary tumor spheroid culture (TSC) reflects colorectal cancer (CRC) heterogeneity As a platform for compound screening, we built up a biobank of 24 primary TSCs
Transcriptome data were available for 21 TSCs, and all consensus molecular subtypes (CMSs) could be detected in our biobank (Figure 1B)

Summary

Introduction

The response of a malignant tumor to drug treatment can be significantly mitigated by cellular heterogeneity (Dagogo-Jack and Shaw, 2018). Individual tumors across multiple tumor types including colorectal cancer (CRC) are built up as a functional hierarchy that comprises cell subfractions with substantial differences in self-renewal capacity and drug sensitivity (Prasetyanti and Medema, 2017). This functional hierarchy with stemcell like tumor-initiating cells (TICs) at the apex is driven by epigenetic changes (e.g., chromatin methylation patterns), as well as paracrine interactions, and influenced by the cell-of-origin in which malignant transformation occurs (Bormann et al, 2018; Prasetyanti and Medema, 2017). There is a strong clinical need for novel compounds with defined activity in genetically and functionally characterized tumor cells

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Discussion

Conclusion