• Deutsch
Login

Open Access

  • Home
  • Search
  • Browse
  • Publish
  • FAQ

Refine

Author

  • Balat, Ahmed el- (1)
  • Becker, Sven (1)
  • Győrffy, Balázs (1)
  • Kaderali, Lars (1)
  • Krämer, Andrea (1)
  • Matthess, Yves (1)
  • Noack, Sabrina (1)
  • Raab, Monika (1)
  • Sanhaji, Mourad (1)
  • Strebhardt, Klaus (1)
+ more

Year of publication

  • 2018 (1)

Document Type

  • Article (1)

Language

  • English (1)

Has Fulltext

  • yes (1)

Is part of the Bibliography

  • no (1)

Keywords

  • cell cycle (1)
  • ovarian cancer (1)
  • paclitaxel (1)
  • protein kinases (1)
  • sensitization (1)

Institute

  • Biowissenschaften (1)
  • Medizin (1)

1 search hit

  • 1 to 1
  • 10
  • 20
  • 50
  • 100
Synthetic lethality in CCNE1-amplified high grade serous ovarian cancer through combined inhibition of Polo-like kinase 1 and microtubule dynamics (2018)
Noack, Sabrina ; Raab, Monika ; Matthess, Yves ; Sanhaji, Mourad ; Krämer, Andrea ; Győrffy, Balázs ; Kaderali, Lars ; Balat, Ahmed el- ; Becker, Sven ; Strebhardt, Klaus
The taxanes are effective microtubule-stabilizing chemotherapy drugs that inhibit mitosis, induce apoptosis, and produce regression in a fraction of cancers that arise at many sites including the ovary. Novel therapeutic targets that augment taxane effects are needed to improve clinical chemotherapy response in CCNE1-amplified high grade serous ovarian cancer (HGSOC) cells. In this study, we conducted an siRNA-based kinome screen to identify modulators of mitotic progression in CCNE1-amplified HGSOC cells that may influence clinical paclitaxel response. PLK1 is overexpressed in many types of cancer, which correlates with poor prognosis. Here, we identified a novel synthetic lethal interaction of the clinical PLK1 inhibitor BI6727 and the microtubule-targeting drug paclitaxel in HGSOC cell lines with CCNE1-amplification and elucidated the underlying molecular mechanisms of this synergism. BI6727 synergistically induces apoptosis together with paclitaxel in different cell lines including a patient-derived primary ovarian cancer culture. Moreover, the inhibition of PLK1 reduced the paclitaxel-induced neurotoxicity in a neurite outgrowth assay. Mechanistically, the combinatorial treatment with BI6727/paclitaxel triggers mitotic arrest, which initiates mitochondrial apoptosis by inactivation of anti-apoptotic BCL-2 family proteins, followed by significant loss of the mitochondrial membrane potential and activation of caspase-dependent effector pathways. This conclusion is supported by data showing that BI6727/paclitaxel-co-treatment stabilizes FBW7, a component of SCF-type ubiquitin ligases that bind and regulate key modulators of cell division and growth including MCL-1 and Cyclin E. This identification of a novel synthetic lethality of PLK1 inhibitors and a microtubule-stabilizing drug has important implications for developing PLK1 inhibitor-based combination treatments in CCNE1-amplified HGSOC cells.
  • 1 to 1

OPUS4 Logo

  • Contact
  • Imprint
  • Sitelinks