dc.contributor.author | Llorca-Cardenosa, MJ | |
dc.contributor.author | Aronson, LI | |
dc.contributor.author | Krastev, DB | |
dc.contributor.author | Nieminuszczy, J | |
dc.contributor.author | Alexander, J | |
dc.contributor.author | Song, F | |
dc.contributor.author | Dylewska, M | |
dc.contributor.author | Broderick, R | |
dc.contributor.author | Brough, R | |
dc.contributor.author | Zimmermann, A | |
dc.contributor.author | Zenke, FT | |
dc.contributor.author | Gurel, B | |
dc.contributor.author | Riisnaes, R | |
dc.contributor.author | Ferreira, A | |
dc.contributor.author | Roumeliotis, T | |
dc.contributor.author | Choudhary, J | |
dc.contributor.author | Pettitt, SJ | |
dc.contributor.author | de Bono, J | |
dc.contributor.author | Cervantes, A | |
dc.contributor.author | Haider, S | |
dc.contributor.author | Niedzwiedz, W | |
dc.contributor.author | Lord, CJ | |
dc.contributor.author | Chong, IY | |
dc.coverage.spatial | United States | |
dc.date.accessioned | 2023-01-04T13:52:35Z | |
dc.date.available | 2023-01-04T13:52:35Z | |
dc.date.issued | 2022-11-02 | |
dc.identifier | 709958 | |
dc.identifier.citation | Cancer Research, 2022, 82 (21), pp. 3962 - 3973 | |
dc.identifier.issn | 0008-5472 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/5640 | |
dc.identifier.eissn | 1538-7445 | |
dc.identifier.eissn | 1538-7445 | |
dc.identifier.doi | 10.1158/0008-5472.CAN-21-4339 | |
dc.description.abstract | UNLABELLED: Gastric cancer represents the third leading cause of global cancer mortality and an area of unmet clinical need. Drugs that target the DNA damage response, including ATR inhibitors (ATRi), have been proposed as novel targeted agents in gastric cancer. Here, we sought to evaluate the efficacy of ATRi in preclinical models of gastric cancer and to understand how ATRi resistance might emerge as a means to identify predictors of ATRi response. A positive selection genome-wide CRISPR-Cas9 screen identified candidate regulators of ATRi resistance in gastric cancer. Loss-of-function mutations in either SMG8 or SMG9 caused ATRi resistance by an SMG1-mediated mechanism. Although ATRi still impaired ATR/CHK1 signaling in SMG8/9-defective cells, other characteristic responses to ATRi exposure were not seen, such as changes in ATM/CHK2, γH2AX, phospho-RPA, or 53BP1 status or changes in the proportions of cells in S- or G2-M-phases of the cell cycle. Transcription/replication conflicts (TRC) elicited by ATRi exposure are a likely cause of ATRi sensitivity, and SMG8/9-defective cells exhibited a reduced level of ATRi-induced TRCs, which could contribute to ATRi resistance. These observations suggest ATRi elicits antitumor efficacy in gastric cancer but that drug resistance could emerge via alterations in the SMG8/9/1 pathway. SIGNIFICANCE: These findings reveal how cancer cells acquire resistance to ATRi and identify pathways that could be targeted to enhance the overall effectiveness of these inhibitors. | |
dc.format | Print | |
dc.format.extent | 3962 - 3973 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER ASSOC CANCER RESEARCH | |
dc.relation.ispartof | Cancer Research | |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.subject | Humans | |
dc.subject | Antineoplastic Agents | |
dc.subject | Ataxia Telangiectasia Mutated Proteins | |
dc.subject | Protein Kinase Inhibitors | |
dc.subject | Protein Serine-Threonine Kinases | |
dc.subject | Stomach Neoplasms | |
dc.subject | Intracellular Signaling Peptides and Proteins | |
dc.title | SMG8/SMG9 Heterodimer Loss Modulates SMG1 Kinase to Drive ATR Inhibitor Resistance. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2022-08-26 | |
dc.date.updated | 2023-01-04T13:51:39Z | |
rioxxterms.version | VoR | |
rioxxterms.versionofrecord | 10.1158/0008-5472.CAN-21-4339 | |
rioxxterms.licenseref.startdate | 2022-11-02 | |
rioxxterms.type | Journal Article/Review | |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/36273494 | |
pubs.issue | 21 | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Biology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Cancer Biomarkers | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Cancer Biomarkers | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Prostate Cancer Targeted Therapy Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Ashworth Collaborators | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Biology/Cancer and Genome Instability | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Biology/Functional Proteomics Group | |
pubs.organisational-group | /ICR/Students | |
pubs.organisational-group | /ICR/Students/PhD and MPhil | |
pubs.organisational-group | /ICR/Students/PhD and MPhil/18/19 Starting Cohort | |
pubs.organisational-group | /ICR/ImmNet | |
pubs.publication-status | Published | |
pubs.publisher-url | http://dx.doi.org/10.1158/0008-5472.can-21-4339 | |
pubs.volume | 82 | |
icr.researchteam | Gene Function | |
icr.researchteam | Cancer Biomarkers | |
icr.researchteam | Functional Proteomics | |
icr.researchteam | Prote & Metabolomics Fac | |
icr.researchteam | PrCa Targeted Therapy | |
icr.researchteam | BCR Bioinformatics Group | |
icr.researchteam | Cancer and Genome Instab | |
icr.researchteam | Ashworth Collaborators | |
dc.contributor.icrauthor | Krastev, Dragomir | |
dc.contributor.icrauthor | Song, Feifei | |
dc.contributor.icrauthor | Gurel, Bora | |
dc.contributor.icrauthor | Roumeliotis, Theodoros | |
dc.contributor.icrauthor | Choudhary, Jyoti | |
dc.contributor.icrauthor | Pettitt, Stephen | |
dc.contributor.icrauthor | De Bono, Johann | |
dc.contributor.icrauthor | Haider, Syed | |
dc.contributor.icrauthor | Niedzwiedz, Wojciech | |
dc.contributor.icrauthor | Lord, Christopher | |
dc.contributor.icrauthor | Chong, Yu-Shing | |
icr.provenance | Deposited by Mr Arek Surman on 2023-01-04. Deposit type is initial. No. of files: 1. Files: 3962.pdf | |