CHK1-targeted therapy to deplete DNA replication-stressed, p53-deficient, hyperdiploid colorectal cancer stem cells
Open accessAbstract
Objective: Cancer stem cells (CSCs) are responsible for tumour formation and spreading, and their targeting is required for tumour eradication. There are limited therapeutic options for advanced colorectal cancer (CRC), particularly for tumours carrying RAS-activating mutations. The aim of this study was to identify novel CSC-targeting strategies. Design: To discover potential therapeutics to be clinically investigated as single agent, we performed a screening with a panel of FDA-approved or investigational drugs on primary CRC cells enriched for CSCs (CRC-SCs) isolated from 27 patients. Candidate predictive biomarkers of efficacy were identified by integrating genomic, reverse-phase protein microarray (RPPA) and cytogenetic analyses, and validated by immunostainings. DNA replication stress (RS) was increased by employing DNA replication-perturbing or polyploidising agents. Results: The drug-library screening led to the identification of LY2606368 as a potent anti-CSC agent acting in vitro and in vivo in tumour cells from a considerable number of patients (∼36%). By inhibiting checkpoint kinase (CHK)1, LY2606368 affected DNA replication in most CRC-SCs, including RAS-mutated ones, forcing them into premature, lethal mitoses. Parallel genomic, RPPA and cytogenetic analyses indicated that CRC-SCs sensitive to LY2606368 displayed signs of ongoing RS response, including the phosphorylation of RPA32 and ataxia telangiectasia mutated serine/threonine kinase (ATM). This was associated with mutation(s) in TP53 and hyperdiploidy, and made these CRC-SCs exquisitely dependent on CHK1 function. Accordingly, experimental increase of RS sensitised resistant CRC-SCs to LY2606368. Conclusions: LY2606368 selectively eliminates replication-stressed, p53-deficient and hyperdiploid CRC-SCs independently of RAS mutational status. These results provide a strong rationale for biomarker-driven clinical trials with LY2606368 in patients with CRC.
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Abrogation of mitotic catastrophe is key in neoplastic transformation/progression by allowing polyploid/aneuploid cells; cancer stem cells have increased sensitivity to mitotic defects.
“Importantly, the abrogation of mitotic catastrophe is a key event during neoplastic transformation and progression, mainly as it allows for the generation and/or survival of polyploid and aneuploid cells [975], whereas cancer (stem) cells reportedly display increased sensitivity to mitotic defects [1003].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [1003]
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Galluzzi, L., Vitale, I., Aaronson, S. A., Abrams, J. M., Adam, D., Agostinis, P., Alnemri, E. S., Altucci, L., Amelio, I., Andrews, D. W., et al. (2018) · Cell Death & Differentiation · doi:10.1038/s41418-017-0012-4 · Cited by 6,680 · see citing works
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- Authors
- Manic, G., Signore, M., Sistigu, A., Russo, G., Corradi, F., Siteni, S., Musella, M., Vitale, S., De Angelis, M. L., Pallocca, M., Amoreo, C. A., Sperati, F., Di Franco, S., Barresi, S., Policicchio, E., De Luca, G., De Nicola, F., Mottolese, M., Zeuner, A., Fanciulli, M., Stassi, G., Maugeri-Saccà, M., Baiocchi, M., Tartaglia, M., Vitale, I., & De Maria, R.
- Affiliations
- University of Rome Tor Vergata (IT)
- Istituto Superiore di Sanità (IT)
- Instituto Nazionale Tumori Regina Elena (IT)
- Agostino Gemelli University Polyclinic (IT)
- Roma Tre University (IT)
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
- Department of Surgical Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy
- Bambino Gesù Children's Hospital (IT)
- SAFU, Department of Research, Advanced Diagnostics, and Technological Innovation, Translational Research Area, Regina Elena National Cancer Institute, Rome Italy
- University of Palermo (IT)
- Division of Medical Oncology 2, Regina Elena National Cancer Institute, Rome, Italy
- Institute of General Pathology, Catholic University and A. Gemelli Polyclinic, Rome, Italy
- Corresponding author
- Vitale, Ilio
- ORCID
- Venue
- Gut
- Publisher
- BMJ
- Published
- 2017-04-07
- Volume
- 67
- Issue
- 5
- Pages
- 903-917
- ISSN
- 0017-5749 (ISSN-L)
- 1468-3288
- PMC
- PMC5890648
- OpenAlex
- W2605017029
- Cited by
- 98
- References
- 51
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 12 · 2023: 6 · 2022: 11 · 2021: 13 · 2020: 9 · 2019: 20 · 2018: 8 · 2017: 8
- FWCI
- 5.42
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Gut (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Nova Science Publishers (Nova Science Publishers, Inc.) (submittedVersion, other-oa)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- PubliCatt (Università Cattolica del Sacro Cuore) (submittedVersion, cc-by-nc)
- Funders
- Ministero dell’Istruzione, dell’Università e della Ricerca
- Associazione Italiana per la Ricerca sul Cancro (14641, 15749, 18418, Start-Up 2016 #18418)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- colorectal cancer stem cells, CHK1 inhibition, replication stress, TP53 mutation, hyperdiploidy, RAS mutations, drug repurposing, predictive biomarkers, ATM phosphorylation, RPA32, polyploidy, anticancer drug screening
- MeSH terms
- Checkpoint Kinase 1, Antineoplastic Agents, DNA Replication, Humans, Immunohistochemistry, Mutation, Pyrazines, Pyrazoles, Neoplastic Stem Cells, Colorectal Neoplasms, Tumor Suppressor Protein p53, Oligonucleotide Array Sequence Analysis, Cell Line, Tumor
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