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|Ref Type||Journal Article|
|Authors||Ralff MD, Kline CLB, Küçükkase OC, Wagner J, Lim B, Dicker DT, Prabhu VV, Oster W, El-Deiry WS|
|Title||ONC201 Demonstrates Antitumor Effects in Both Triple-Negative and Non-Triple-Negative Breast Cancers through TRAIL-Dependent and TRAIL-Independent Mechanisms.|
|Journal||Molecular cancer therapeutics|
|Abstract Text||Breast cancer is a major cause of cancer-related death. TNF-related apoptosis-inducing ligand (TRAIL) has been of interest as a cancer therapeutic, but only a subset of triple-negative breast cancers (TNBC) is sensitive to TRAIL. The small-molecule ONC201 induces expression of TRAIL and its receptor DR5. ONC201 has entered clinical trials in advanced cancers. Here, we show that ONC201 is efficacious against both TNBC and non-TNBC cells (n = 13). A subset of TNBC and non-TNBC cells succumbs to ONC201-induced cell death. In 2 of 8 TNBC cell lines, ONC201 treatment induces caspase-8 cleavage and cell death that is blocked by TRAIL-neutralizing antibody RIK2. The proapoptotic effect of ONC201 translates to in vivo efficacy in the MDA-MB-468 xenograft model. In most TNBC lines tested (6/8), ONC201 has an antiproliferative effect but does not induce apoptosis. ONC201 decreases cyclin D1 expression and causes an accumulation of cells in the G1 phase of the cell cycle. pRb expression is associated with sensitivity to the antiproliferative effects of ONC201, and the compound synergizes with taxanes in less sensitive cells. All non-TNBC cells (n = 5) are growth inhibited following ONC201 treatment, and unlike what has been observed with TRAIL, a subset (n = 2) shows PARP cleavage. In these cells, cell death induced by ONC201 is TRAIL independent. Our data demonstrate that ONC201 has potent antiproliferative and proapoptotic effects in a broad range of breast cancer subtypes, through TRAIL-dependent and TRAIL-independent mechanisms. These findings develop a preclinical rationale for developing ONC201 as a single agent and/or in combination with approved therapies in breast cancer. Mol Cancer Ther; 16(7); 1290-8. ©2017 AACR.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||triple-receptor negative breast cancer||not applicable||ONC201||Preclinical - Cell line xenograft||Actionable||In a preclinical study, ONC201 inhibited viability of several triple-negative breast cancer (TNBC) cell lines in culture, demonstrating variable pro-apototic and anti-proliferative activity, and inhibited tumor growth in TNBC cell line xenograft models (PMID: 28424227).||28424227|
|Unknown unknown||triple-receptor negative breast cancer||not applicable||ONC201 + Paclitaxel||Preclinical - Cell culture||Actionable||In a preclinical study, the combination of ONC201 and Taxol (paclitaxel) worked synergistically to inhibit viability of triple-negative breast cancer cell lines in culture (PMID: 28424227).||28424227|
|Unknown unknown||breast cancer||not applicable||ONC201||Preclinical - Cell line xenograft||Actionable||In a preclinical study, ONC201 inhibited viability of several breast cancer cell lines in culture (including triple-negative breast cancer (TNBC) and non-TNBC cell lines), with some cell lines demonstrating increased apoptosis, and inhibited tumor growth in TNBC cell line xenograft models (PMID: 28424227).||28424227|
|Unknown unknown||triple-receptor negative breast cancer||not applicable||Docetaxel + ONC201||Preclinical - Cell culture||Actionable||In a preclinical study, the combination of ONC201 and Docefrez (docetaxel) worked synergistically to inhibit viability of triple-negative breast cancer cell lines in culture (PMID: 28424227).||28424227|