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Metronomic dosing of ovarian cancer cells with the ATR inhibitor AZD6738 leads to loss of CDC25A expression and resistance to ATRi treatment.
Ao, Wei; Kim, Hong Im; Tommarello, Domenic; Conrads, Kelly A; Hood, Brian L; Litzi, Tracy; Abulez, Tamara; Teng, Pang-Ning; Dalgard, Clifton L; Zhang, Xijun; Wilkerson, Matthew D; Darcy, Kathleen M; Tarney, Christopher M; Phippen, Neil T; Bakkenist, Christopher J; Maxwell, G Larry; Conrads, Thomas P; Risinger, John I; Bateman, Nicholas W.
Afiliação
  • Ao W; Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda 20889, MD, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. Bethes
  • Kim HI; Department of Obstetrics, Gynecology and Reproductive Biology, College of Human Medicine, Michigan State University Grand Rapids, MI, USA.
  • Tommarello D; Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda 20889, MD, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. Bethes
  • Conrads KA; Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda 20889, MD, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. Bethes
  • Hood BL; Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda 20889, MD, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. Bethes
  • Litzi T; Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda 20889, MD, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. Bethes
  • Abulez T; Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda 20889, MD, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. Bethes
  • Teng PN; Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda 20889, MD, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. Bethes
  • Dalgard CL; The American Genome Center, Department of Anatomy Physiology and Genetics, Collaborative Health Initiative Research Program, Uniformed Services University, 4301 Jones Bridge Road, Bethesda, MD 20814, USA.
  • Zhang X; The American Genome Center, Department of Anatomy Physiology and Genetics, Collaborative Health Initiative Research Program, Uniformed Services University, 4301 Jones Bridge Road, Bethesda, MD 20814, USA.
  • Wilkerson MD; The American Genome Center, Department of Anatomy Physiology and Genetics, Collaborative Health Initiative Research Program, Uniformed Services University, 4301 Jones Bridge Road, Bethesda, MD 20814, USA.
  • Darcy KM; Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda 20889, MD, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. Bethes
  • Tarney CM; Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda 20889, MD, USA; The John P. Murtha Cancer Center, Uniformed Services University and Walter Reed N
  • Phippen NT; Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda 20889, MD, USA; The John P. Murtha Cancer Center, Uniformed Services University and Walter Reed N
  • Bakkenist CJ; Departments of Radiation Biology and Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
  • Maxwell GL; Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda 20889, MD, USA; The John P. Murtha Cancer Center, Uniformed Services University and Walter Reed N
  • Conrads TP; Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda 20889, MD, USA; The John P. Murtha Cancer Center, Uniformed Services University and Walter Reed N
  • Risinger JI; Department of Obstetrics, Gynecology and Reproductive Biology, College of Human Medicine, Michigan State University Grand Rapids, MI, USA.
  • Bateman NW; Gynecologic Cancer Center of Excellence, Department of Gynecologic Surgery and Obstetrics, Uniformed Services University and Walter Reed National Military Medical Center, 8901 Wisconsin Avenue, Bethesda 20889, MD, USA; Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. Bethes
Gynecol Oncol ; 177: 60-71, 2023 Oct.
Article em En | MEDLINE | ID: mdl-37639904
ABSTRACT

OBJECTIVE:

ATR kinase inhibitors promote cell killing by inducing replication stress and through potentiation of genotoxic agents in gynecologic cancer cells. To explore mechanisms of acquired resistance to ATRi in ovarian cancer, we characterized ATRi-resistant ovarian cancer cells generated by metronomic dosing with the clinical ATR inhibitor AZD6738.

METHODS:

ATRi-resistant ovarian cancer cells (OVCAR3 and OV90) were generated by dosing with AZD6738 and assessed for sensitivity to Chk1i (LY2603618), PARPi (Olaparib) and combination with cisplatin or a CDK4/6 inhibitor (Palbociclib). Models were characterized by diverse methods including silencing CDC25A in OV90 cells and assessing impact on ATRi response. Serum proteomic analysis of ATRi-resistant OV90 xenografts was performed to identify circulating biomarker candidates of ATRi-resistance.

RESULTS:

AZD6738-resistant cell lines are refractory to LY2603618, but not to Olaparib or combinations with cisplatin. Cell cycle analyses showed ATRi-resistant cells exhibit G1/S arrest following AZD6738 treatment. Accordingly, combination with Palbociclib confers resistance to AZD6738. AZD6738-resistant cells exhibit altered abundances of G1/S phase regulatory proteins, including loss of CDC25A in AZD6738-resistant OV90 cells. Silencing of CDC25A in OV90 cells confers resistance to AZD6738. Serum proteomics from AZD6738-resistant OV90 xenografts identified Vitamin D-Binding Protein (GC), Apolipoprotein E (APOE) and A1 (APOA1) as significantly elevated in AZD6738-resistant backgrounds.

CONCLUSIONS:

We show that metronomic dosing of ovarian cancer cells with AZD6738 results in resistance to ATR/ Chk1 inhibitors, that loss of CDC25A expression represents a mechanism of resistance to ATRi treatment in ovarian cancer cells and identify several circulating biomarker candidates of CDC25A low, AZD6738-resistant ovarian cancer cells.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Ano de publicação: 2023 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Ano de publicação: 2023 Tipo de documento: Article