Abstract 5314: A novel dopamine receptor D2 antagonist (ONC206) potentiates the effects of olaparib in endometrial cancer cells through inhibition of cell proliferation and modulation of the mTOR pathway

• Published in: Cancer research (Chicago, Ill.) Ill.), 2020-08, Vol.80 (16_Supplement), p.5314-5314
• Main Authors: Paraghamian, Sarah E., Hawkins, Gabrielle M., Sun, Wenchuan, Fan, Yali, Zhang, Xin, Suo, Hongyan, Prabhu, Varun Vijay, Allen, Joshua E., Zhou, Chunxiao, Bae-Jump, Victoria
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2020-5314

Objectives: Poly ADP-ribose polymerase (PARP) inhibitors are effective therapies for patients with homologous recombination (HR) deficient tumors. While HR mutations are rare in endometrial cancers (ECs), emerging data suggests that loss of function of the tumor suppressor gene Phosphatase and Tensin homolog (PTEN), which is mutated in 80% of endometrioid ECs, may also sensitize tumors to PARP inhibition. The imipridone ONC206, a chemical derivative of ONC201, is an orally bioavailable dopamine receptor D2 (DRD2) antagonist that has anti-tumorigenic effects in EC via induction of apoptosis and activation of the integrated stress response. ONC206 exhibits enhanced non-competitive DRD2 antagonism, potency, and bioavailability relative to ONC201. Both olaparib and imipridones (i.e. ONC201) are being evaluated in EC clinical trials, but have yet to be explored in combination. Thus, we sought to examine the effects of olaparib in combination with ONC206 in human endometrioid EC cell lines. Methods: The ECC-1 and HEC-1 EC cell lines were used. Cell proliferation was assessed after exposure to varying doses of olaparib (MedChemExpress) and ONC206 (Oncoceutics) via the MTT assay. Synergy between olaparib and ONC206 was assessed by the combination index (CI) method of Chou-Talalay. Cellular stress was evaluated using the DCFH-DA assay. Apoptosis was assessed using the cleaved caspase-3 assay. Western immunoblotting was performed to determine effects of olaparib and ONC206 on apoptosis and the mTOR pathway. Results: Both drugs inhibited cell proliferation in a dose-dependent manner (IC50 for olaparib of 15 uM for ECC-1 and 25 uM for HEC-1; IC50 for ONC206 of 3.3 uM for ECC-1 and 0.9 uM for HEC-1). Simultaneous exposure of OC cells to ONC206 and olaparib at low doses resulted in synergistic anti-proliferative effects (CI