Combined casein kinase II and MAPK signalling inhibition as a therapeutic strategy for metastatic colorectal cancer
10 affiliations
- 1Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland
- 2Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CG Utrecht, The Netherlands
- 3Oncode Institute, Utrecht, The Netherlands
- 4IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, Milan, 20089 Italy
- 5Institute of Medical Genetics and Pathology, University Hospital Basel, University of Basel, Basel, Switzerland
- 6Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland
- 7Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Milan, Italy
- 8Faculty of Medicine, University of Basel, Klingelbergstrasse 61, Basel, 4056 Switzerland
- 9Department of Visceral Surgery, Clarunis, University Centre for Gastrointestinal and Liver Diseases, St. Clara Hospital and University Hospital Basel, Basel, Switzerland
- 10Kantonsspital Baselland, Liestal, 4410 Switzerland
Abstract
Background: Metastatic colorectal cancer (mCRC) remains a significant clinical challenge due to the emergence of drug resistance, highlighting the need for new therapeutic strategies. Aberrant regulation of the proteome drives cancer progression, and dissecting these alterations offers opportunities for targeted intervention. We aimed to identify candidate kinase dependencies in mCRC and to test a rational combination strategy in patient-derived models.
Methods: We performed proteomic and phosphoproteomic profiling of 10 mCRC tissues, their matched patient-derived organoids (PDOs) and normal colon mucosa, integrated with whole-exome sequencing. Kinase activities were inferred by kinase-substrate enrichment analysis. Silmitasertib-mediated casein kinase II (CKII) inhibition, alone and combined with the MEK inhibitor trametinib, was evaluated by ex vivo drug screening, western blot, flow cytometry and drug-interaction analysis across the PDO cohort and in normal colon PDOs.
Results: PDOs recapitulated the molecular features of matched tumours. Both tissues and PDOs showed consistently elevated CKII activity. Silmitasertib exerted heterogeneous antitumour activity, and resistance was associated with MAPK and Akt-mTOR signalling activity. Combining silmitasertib with trametinib produced an additive reduction of both resistance-associated pathways with little effect on the viability of normal colon PDOs. The combination also significantly reduced CKII activity, the abundance of active β-catenin and the colorectal cancer stem cell pool.
Conclusions: Phosphoproteomic profiling identified CKII as a therapeutic vulnerability in mCRC and provided a rationale for combining silmitasertib with MEK inhibition, offering a candidate combination strategy for mCRC.
Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s40164-026-00855-4.
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BibTeX
@article{marinucci2026combined,
title = {{Combined casein kinase II and MAPK signalling inhibition as a therapeutic strategy for metastatic colorectal cancer}},
author = {Mattia Marinucci and Federico Donà and Gina F. Boot and Cinzia Esposito and Elenia Toccafondi and Daniela Liberati and Andrej Benjak and Lara Zaidi and Melania Lazzari and Giulia Milardi and Karolina Guja-Jarosz and Miriam Cieri and Huiche Feng and Mairene Coto-Llerena and Raoul A. Droeser and Savas D. Soysal and Otto Kollmar and Guido Torzilli and Antonino Spinelli and Luigi M. Terracciano and Charlotte K. Y. Ng and Salvatore Piscuoglio},
journal = {Experimental Hematology \& Oncology},
year = {2026},
month = nov,
doi = {10.1186/s40164-026-00855-4},
url = {https://doi.org/10.1186/s40164-026-00855-4},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Combined casein kinase II and MAPK signalling inhibition as a therapeutic strategy for metastatic colorectal cancer
AU - Mattia Marinucci
AU - Federico Donà
AU - Gina F. Boot
AU - Cinzia Esposito
AU - Elenia Toccafondi
AU - Daniela Liberati
AU - Andrej Benjak
AU - Lara Zaidi
AU - Melania Lazzari
AU - Giulia Milardi
AU - Karolina Guja-Jarosz
AU - Miriam Cieri
AU - Huiche Feng
AU - Mairene Coto-Llerena
AU - Raoul A. Droeser
AU - Savas D. Soysal
AU - Otto Kollmar
AU - Guido Torzilli
AU - Antonino Spinelli
AU - Luigi M. Terracciano
AU - Charlotte K. Y. Ng
AU - Salvatore Piscuoglio
PY - 2026
DA - 2026/11/05
JO - Experimental Hematology & Oncology
DO - 10.1186/s40164-026-00855-4
UR - https://doi.org/10.1186/s40164-026-00855-4
AB - Background: Metastatic colorectal cancer (mCRC) remains a significant clinical challenge due to the emergence of drug resistance, highlighting the need for new therapeutic strategies. Aberrant regulation of the proteome drives cancer progression, and dissecting these alterations offers opportunities for targeted intervention. We aimed to identify candidate kinase dependencies in mCRC and to test a rational combination strategy in patient-derived models. Methods: We performed proteomic and phosphoproteomic profiling of 10 mCRC tissues, their matched patient-derived organoids (PDOs) and normal colon mucosa, integrated with whole-exome sequencing. Kinase activities were inferred by kinase-substrate enrichment analysis. Silmitasertib-mediated casein kinase II (CKII) inhibition, alone and combined with the MEK inhibitor trametinib, was evaluated by ex vivo drug screening, western blot, flow cytometry and drug-interaction analysis across the PDO cohort and in normal colon PDOs. Results: PDOs recapitulated the molecular features of matched tumours. Both tissues and PDOs showed consistently elevated CKII activity. Silmitasertib exerted heterogeneous antitumour activity, and resistance was associated with MAPK and Akt-mTOR signalling activity. Combining silmitasertib with trametinib produced an additive reduction of both resistance-associated pathways with little effect on the viability of normal colon PDOs. The combination also significantly reduced CKII activity, the abundance of active β-catenin and the colorectal cancer stem cell pool. Conclusions: Phosphoproteomic profiling identified CKII as a therapeutic vulnerability in mCRC and provided a rationale for combining silmitasertib with MEK inhibition, offering a candidate combination strategy for mCRC. Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s40164-026-00855-4.
SN - 2162-3619
ER -