Abstract 4294: Preclinical evaluation of imipridone ONC201 in triple negative breast cancer identifies predictive biomarkers and combinatorial opportunities
Authors: Lim Bora , Lee Jangsoon , Liu Huey , Pearson Troy , Coffer Larry , Tripathy Debu , Ueno Naoto T. 
Published: July 2017

Background: Triple negative breast cancer (TNBC) lacks effective targeted therapy, leaving chemotherapy as the only therapeutic option. Metastatic TNBCs eventually develop resistance to chemotherapy via several mechanisms including apoptosis evasion, hence representing an urgent unmet need for novel therapies. ONC201 is a first-in-class imipridone that induces caspase-mediated apoptosis in multiple cancers including TNBC, selectively antagonizing dopamine D2-like receptors (DRD2) resulting in inhibition of Ras signaling and cell death. Selective antagonism of D2-like receptors has been shown to induce cell death in cancer cells via the same signaling pathways engaged by ONC201. To translate these early findings for breast cancers patients, more studies to prove ONC201’s activity and mechanism of action in breast cancers are needed. In this study, we tested the efficacy of ONC201 in TNBC cell lines, and further confirmed the mechanism of action of ONC201 by studying the association between DRD2/DRD5 and ONC201 efficacy. Additionally, we performed siRNA kinome screening to identify combinatorial opportunities to further enhance ONC201 efficacy in TNBC.

Method: We determined the efficacy of ONC201 in 20 TNBC cell lines by determining the IC50. We then selected one cell line with low IC50 (CAL51) and high IC50 (HCC70) for siRNA synthetic lethality screening via 2D and 3D culture systems. Additionally, we correlated the IC50 with the mRNA expression of DRD2 measured by Affymetrix microarray on each TNBC cell lines with IC50 of the ONC201. Result: IC50 ranged from 2.09 to 40μM, with median IC50 of 10μM. No correlation between Vanderbilt TNBC molecular subtype and IC50. 2D/3D siRNA kinome screening and Ingenuity pathway analysis showed PIK3, MAPK, and Ephrin receptor pathways as top three target candidates correlating with tumor growth inhibition efficacy of ONC201. The long variant of DRD2 mRNA expression and ONC201 IC50 showed a correlation. There was a negative correlation between mRNA expression of DRD5 and IC50 (R2=0.3601, P=0.018).

Conclusion: Our preclinical results suggest that ONC201 is active is TNBC cells within previously proven safe therapeutic dose and provides potential combinatorial opportunities with PI3K/MAPK targeted drugs. These results highlight the importance of targeting the dopamine receptor pathway for ONC201 efficacy and supports DRD5 as a potential predictive marker. Targeting DRD2 and apoptosis induction could be one of therapeutic strategy in triple negative breast cancers. Ongoing work involves further in vitro and in vivo studies to determine the best synergistic therapeutic partner and conducting a phase II single agent trial to study the pharmacodynamics changes induced by ONC201 in TNBC.

Citation Format: Bora Lim, Jangsoon Lee, Huey Liu, Troy Pearson, Larry Coffer, Debu Tripathy, Naoto T. Ueno. Preclinical evaluation of imipridone ONC201 in triple negative breast cancer identifies predictive biomarkers and combinatorial opportunities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4294. doi:10.1158/1538-7445.AM2017-4294