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Enhanced Efficacy of Aurora Kinase Inhibitors in G2/M Checkpoint Deficient TP53 Mutant Uterine Carcinomas Is Linked to the Summation of LKB1-AKT-p53 Interactions.
Lynch, Katherine N; Liu, Joyce F; Kesten, Nikolas; Chow, Kin-Hoe; Shetty, Aniket; He, Ruiyang; Afreen, Mosammat Faria; Yuan, Liping; Matulonis, Ursula A; Growdon, Whitfield B; Muto, Michael G; Horowitz, Neil S; Feltmate, Colleen M; Worley, Michael J; Berkowitz, Ross S; Crum, Christopher P; Rueda, Bo R; Hill, Sarah J.
Afiliación
  • Lynch KN; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Liu JF; Division of Molecular and Cellular Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Kesten N; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Chow KH; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
  • Shetty A; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • He R; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Afreen MF; Center for Patient Derived Models, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Yuan L; Center for Patient Derived Models, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Matulonis UA; Department of Biochemistry, Cambridge University, Cambridge CB2 1QW, UK.
  • Growdon WB; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Muto MG; Division of Molecular and Cellular Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Horowitz NS; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
  • Feltmate CM; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Worley MJ; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
  • Berkowitz RS; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Crum CP; Vincent Center for Reproductive Biology, Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Rueda BR; Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, MA 02115, USA.
  • Hill SJ; Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School, Boston, MA 02115, USA.
Cancers (Basel) ; 13(9)2021 May 03.
Article en En | MEDLINE | ID: mdl-34063609
Uterine carcinoma (UC) is the most common gynecologic malignancy in the United States. TP53 mutant UCs cause a disproportionate number of deaths due to limited therapies for these tumors and the lack of mechanistic understanding of their fundamental vulnerabilities. Here we sought to understand the functional and therapeutic relevance of TP53 mutations in UC. We functionally profiled targetable TP53 dependent DNA damage repair and cell cycle control pathways in a panel of TP53 mutant UC cell lines and patient-derived organoids. There were no consistent defects in DNA damage repair pathways. Rather, most models demonstrated dependence on defective G2/M cell cycle checkpoints and subsequent upregulation of Aurora kinase-LKB1-p53-AKT signaling in the setting of baseline mitotic defects. This combination makes them sensitive to Aurora kinase inhibition. Resistant lines demonstrated an intact G2/M checkpoint, and combining Aurora kinase and WEE1 inhibitors, which then push these cells through mitosis with Aurora kinase inhibitor-induced spindle defects, led to apoptosis in these cases. Overall, this work presents Aurora kinase inhibitors alone or in combination with WEE1 inhibitors as relevant mechanism driven therapies for TP53 mutant UCs. Context specific functional assessment of the G2/M checkpoint may serve as a biomarker in identifying Aurora kinase inhibitor sensitive tumors.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Cancers (Basel) Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Suiza
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Cancers (Basel) Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Suiza