Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 903-917 |
| Number of pages | 15 |
| Journal | Gut |
| Volume | 67 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - 2018 |
Keywords
- CELL CYCLE CONTROL
- CHEMOTHERAPY
- COLORECTAL CANCER
- DNA DAMAGE
- DRUG DEVELOPMENT
- ATM protein
- checkpoint kinase 1
- oncoprotein
- prexasertib
- protein p53
- protein RPA32
- tumor marker
- unclassified drug
- antineoplastic agent
- CHEK1 protein, human
- pyrazine derivative
- pyrazole derivative
- animal cell
- animal experiment
- animal model
- animal tissue
- antineoplastic activity
- Article
- cancer cell destruction
- cancer resistance
- cancer screening
- cancer stem cell
- chemosensitivity
- colorectal cancer
- controlled study
- cytogenetics
- DNA damage
- DNA library
- DNA replication
- enzyme phosphorylation
- genome analysis
- human
- human cell
- immunohistochemistry
- in vitro study
- in vivo study
- mitosis
- mutational analysis
- nonhuman
- priority journal
- protein microarray
- protein phosphorylation
- sensitivity analysis
- colorectal tumor
- DNA microarray
- drug effect
- genetics
- metabolism
- mutation
- tumor cell line
- Antineoplastic Agents
- Cell Line, Tumor
- Checkpoint Kinase 1
- Colorectal Neoplasms
- DNA Replication
- Humans
- Immunohistochemistry
- Mutation
- Neoplastic Stem Cells
- Oligonucleotide Array Sequence Analysis
- Pyrazines
- Pyrazoles
- Tumor Suppressor Protein p53
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CHK1-targeted therapy to deplete DNA replication-stressed, p53-deficient, hyperdiploid colorectal cancer stem cells. / 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.
In: Gut, Vol. 67, No. 5, 2018, p. 903-917.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - CHK1-targeted therapy to deplete DNA replication-stressed, p53-deficient, hyperdiploid colorectal cancer stem cells
AU - Manic, G.
AU - Signore, M.
AU - Sistigu, A.
AU - Russo, G.
AU - Corradi, F.
AU - Siteni, S.
AU - Musella, M.
AU - Vitale, S.
AU - De Angelis, M.L.
AU - Pallocca, M.
AU - Amoreo, C.A.
AU - Sperati, F.
AU - Di Franco, S.
AU - Barresi, S.
AU - Policicchio, E.
AU - De Luca, G.
AU - De Nicola, F.
AU - Mottolese, M.
AU - Zeuner, A.
AU - Fanciulli, M.
AU - Stassi, G.
AU - Maugeri-Saccà, M.
AU - Baiocchi, M.
AU - Tartaglia, M.
AU - Vitale, I.
AU - De Maria, R.
N1 - Cited By :11 Export Date: 11 April 2019 CODEN: GUTTA Correspondence Address: Vitale, I.; Department of Biology, University of Rome 'Tor Vergata', Ricerca Scientifica 1, Italy; email: iliovit@gmail.com Chemicals/CAS: prexasertib, 1234015-52-1; Antineoplastic Agents; Checkpoint Kinase 1; CHEK1 protein, human; prexasertib; Pyrazines; Pyrazoles; Tumor Suppressor Protein p53 Tradenames: ly 2606368, Lilly, United States Manufacturers: Lilly, United States Funding details: Australian Catholic University Funding details: Ministero della Salute, RF_GR-2011-02351355 Funding details: RBAP11WCRZ-005 U54 2010, 15749, GM, 18418 Funding details: Ministero dell’Istruzione, dell’Università e della Ricerca, MIUR Funding details: Associazione Italiana per la Ricerca sul Cancro Funding details: Associazione Italiana per la Ricerca sul Cancro, 9979, MT, 14641 Funding text 1: DNA replication, RS response and cell cycle progression.36 37 We surmise that the essential role of CHK1 in CRC-SCs is to maintain a high but tolerable level of RS (figure 7F). This ‘threshold level’ hypothesis is supported by two observations. First, LY2606368-mediated inhibition of CHK1 increased the level of RS and induced a lethal replication catastrophe31 exclusively in CRC-SCs responding to LY2606368. This occurred through a Funding text 2: 1Department of Biology, University of Rome “Tor Vergata”, Rome, Italy 2Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy 3Department of Research, Advanced Diagnostics and Technological Innovation, Regina Elena National Cancer Institute, Rome, Italy 4Institute of General Pathology, Catholic University and A. Gemelli Polyclinic, Rome, Italy 5Department of Science, University “Roma Tre”, Rome, Italy 6Department of Molecular Medicine, University “La Sapienza”, Rome, Italy 7SAFU, Department of Research, Advanced Diagnostics, and Technological Innovation, Translational Research Area, Regina Elena National Cancer Institute, Rome Italy 8Department of Pathology, Regina Elena National Cancer Institute, Rome, Italy 9Biostatistical Unit, Regina Elena National Cancer Institute, Rome, Italy 10Department of Surgical Oncological and Stomatological Sciences, University of Palermo, Palermo, Italy 11Genetics and Rare Diseases Research Division, Ospedale Pediatrico “Bambino Gesù”, Rome, Italy 12Department of Experimental Medicine, University “La Sapienza”, Rome, Italy 13Division of Medical Oncology 2, Regina Elena National Cancer Institute, Rome, Italy Funding text 3: Funding This work was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC, MFAG 2013 grant number 14641 to IV, 5 per Mille grant number 9979 to GS, MT and RDM), Ministero Italiano della Salute (grant number RF_GR-2011-02351355 to IV), Ministero Italiano dell’Istruzione, dell’Universita e della Ricerca (MIUR, Programma per i Giovani Ricercatori ‘Rita Levi Montalcini’ 2010 to IV and Fondo per gli Investimenti della Ricerca di Base, FIRB, grant number RBAP11WCRZ-005 U54 2010 to RDM). AS is supported by AIRC (Start-Up 2016 #18418). GM is supported by AIRC (Triennial Fellowship ‘Antonietta Latronico’ 2014). AZ is supported by AIRC (grant number 15749). SDF is an AIRC fellowship recipient for 2016. 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PY - 2018
Y1 - 2018
N2 - 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. © 2018 Published by the BMJ Publishing Group Limited.
AB - 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. © 2018 Published by the BMJ Publishing Group Limited.
KW - CELL CYCLE CONTROL
KW - CHEMOTHERAPY
KW - COLORECTAL CANCER
KW - DNA DAMAGE
KW - DRUG DEVELOPMENT
KW - ATM protein
KW - checkpoint kinase 1
KW - oncoprotein
KW - prexasertib
KW - protein p53
KW - protein RPA32
KW - tumor marker
KW - unclassified drug
KW - antineoplastic agent
KW - CHEK1 protein, human
KW - pyrazine derivative
KW - pyrazole derivative
KW - animal cell
KW - animal experiment
KW - animal model
KW - animal tissue
KW - antineoplastic activity
KW - Article
KW - cancer cell destruction
KW - cancer resistance
KW - cancer screening
KW - cancer stem cell
KW - chemosensitivity
KW - colorectal cancer
KW - controlled study
KW - cytogenetics
KW - DNA damage
KW - DNA library
KW - DNA replication
KW - enzyme phosphorylation
KW - genome analysis
KW - human
KW - human cell
KW - immunohistochemistry
KW - in vitro study
KW - in vivo study
KW - mitosis
KW - mutational analysis
KW - nonhuman
KW - priority journal
KW - protein microarray
KW - protein phosphorylation
KW - sensitivity analysis
KW - colorectal tumor
KW - DNA microarray
KW - drug effect
KW - genetics
KW - metabolism
KW - mutation
KW - tumor cell line
KW - Antineoplastic Agents
KW - Cell Line, Tumor
KW - Checkpoint Kinase 1
KW - Colorectal Neoplasms
KW - DNA Replication
KW - Humans
KW - Immunohistochemistry
KW - Mutation
KW - Neoplastic Stem Cells
KW - Oligonucleotide Array Sequence Analysis
KW - Pyrazines
KW - Pyrazoles
KW - Tumor Suppressor Protein p53
U2 - 10.1136/gutjnl-2016-312623
DO - 10.1136/gutjnl-2016-312623
M3 - Article
VL - 67
SP - 903
EP - 917
JO - Gut
JF - Gut
SN - 0017-5749
IS - 5
ER -