Targeting Dopamine Receptor D2 by Imipridone Suppresses Uterine Serous Cancer Malignant Phenotype.
Wen HuLi ZhangSammy Ferri-BorgognoSuet-Ying KwanKelsey E LewisHan T CunTsz-Lun YeungPamela T SolimanRohinton S TaraporeJoshua E AllenXinyuan GuanKaren H LuSamuel C MokChi-Lam Au-YeungPublished in: Cancers (2020)
Uterine serous cancer (USC) is an aggressive subtype of endometrial cancer, with poor survival and high recurrence rates. The development of novel and effective therapies specific to USC would aid in its management. However, few studies have focused solely on this rare subtype. The current study demonstrated that the orally bioavailable, investigational new drug and novel imipridone ONC206 suppressed USC cell proliferation and induced apoptosis both in vitro and in vivo. Disruption of the DRD2-mediated p38MAPK/ERK/PGC-1α network by ONC206 led to metabolic reprogramming and suppression of both glycolysis and oxidative phosphorylation. ONC206 also synergized with paclitaxel in reducing USC cell viability. In addition, DRD2 overexpression correlated with poor overall survival in patients. This study provides the first evidence that ONC206 induced metabolic reprogramming in USC cells and is a promising therapeutic agent for USC treatment. These findings support further development of ONC206 as a promising therapeutic agent and improves survival rates in patients with USC.
Keyphrases
- induced apoptosis
- cell proliferation
- signaling pathway
- endometrial cancer
- endoplasmic reticulum stress
- papillary thyroid
- free survival
- high grade
- oxidative stress
- end stage renal disease
- pi k akt
- newly diagnosed
- ejection fraction
- squamous cell
- squamous cell carcinoma
- transcription factor
- diabetic rats
- high glucose
- cancer therapy
- study protocol
- replacement therapy