SMG8/SMG9 Heterodimer Loss Modulates SMG1 Kinase to Drive ATR Inhibitor Resistance.
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Date
2022-11-02ICR Author
Author
Llorca-Cardenosa, MJ
Aronson, LI
Krastev, DB
Nieminuszczy, J
Alexander, J
Song, F
Dylewska, M
Broderick, R
Brough, R
Zimmermann, A
Zenke, FT
Gurel, B
Riisnaes, R
Ferreira, A
Roumeliotis, T
Choudhary, J
Pettitt, SJ
de Bono, J
Cervantes, A
Haider, S
Niedzwiedz, W
Lord, CJ
Chong, IY
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Subject
Humans
Antineoplastic Agents
Ataxia Telangiectasia Mutated Proteins
Protein Kinase Inhibitors
Protein Serine-Threonine Kinases
Stomach Neoplasms
Intracellular Signaling Peptides and Proteins
Research team
Gene Function
Cancer Biomarkers
Functional Proteomics
Prote & Metabolomics Fac
PrCa Targeted Therapy
BCR Bioinformatics Group
Cancer and Genome Instab
Ashworth Collaborators
Language
eng
Date accepted
2022-08-26
License start date
2022-11-02
Citation
Cancer Research, 2022, 82 (21), pp. 3962 - 3973
Publisher
AMER ASSOC CANCER RESEARCH