Priority Research Papers:
TRAIL receptor agonists convert the response of breast cancer cells to ONC201 from anti-proliferative to apoptotic
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Abstract
Marie D. Ralff1,2, Aakash Jhaveri3,4,5, Jocelyn E. Ray2,6, Lanlan Zhou2,4,5,10, Avital Lev2, Kerry S. Campbell7, David T. Dicker2,4,5, Eric A. Ross8 and Wafik S. El-Deiry2,4,5,9,10
1 MD/PhD Program, The Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA
2 Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Medical Oncology and Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, USA
3 Master of Science in Biotechnology Program, The Warren Alpert Medical School, Brown University, Providence, RI, USA
4 Joint Program in Cancer Biology, Brown University and the Lifespan Health System, Providence, RI, USA
5 Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Pathology and Laboratory Medicine, The Warren Alpert Medical School, Brown University, Providence, RI, USA
6 Division of Gynecologic Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
7 Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA, USA
8 Biostatistics and Bioinformatics Facility, Fox Chase Cancer Center, Philadelphia, PA, USA
9 Hematology-Oncology Division, Brown University and the Lifespan Cancer Institute, Providence, RI, USA
10 Cancer Center at Brown University, The Warren Alpert Medical School, Brown University, Providence, RI, USA
Correspondence to:
| Wafik S. El-Deiry, | email: | [email protected] |
Keywords: ONC201; TRAIL; breast cancer; death receptors; apoptosis
Received: September 23, 2020 Accepted: October 07, 2020 Published: October 20, 2020
ABSTRACT
ONC201 was initially identified as an inducer of cell death through the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) pathway. The compound is currently being tested in patients with hematological malignancies and solid tumors, including those of the breast. We investigated strategies to convert the response of breast cancers to ONC201 from anti-proliferative to apoptotic. ONC201 treatment upregulates TRAIL and primes TRAIL-resistant non-triple negative breast cancer (TNBC) cells to undergo cell death through the extrinsic pathway. Remarkably, the addition of exogenous recombinant human TRAIL (rhTRAIL) converts the response of TRAIL-resistant non-TNBC cells to ONC201 from anti-proliferative to apoptotic in a death receptor 5 (DR5)-dependent manner in vitro. Importantly, normal fibroblasts do not undergo apoptosis following rhTRAIL plus ONC201. In vivo, MDA-MB-361 tumor growth rate is significantly reduced following treatment with a combination of ONC201 and rhTRAIL as compared to control tumors. Natural killer (NK) cells which use TRAIL to kill DR5-expressing cancer cells, exhibit greater cytotoxicity against ONC201-treated breast cancer cells compared to controls. rhTRAIL also converts the response of cells from other tumor types to ONC201 from anti-proliferative to apoptotic. A monoclonal DR5-agonistic antibody converts the response of non-TNBC cells to ONC201 from anti-proliferative to apoptotic. Our findings describe a novel therapeutic strategy that potently converts the response of a cancer cell to ONC201 from anti-proliferative to apoptotic. This approach may be clinically relevant and has potential to induce tumor regression of patient tumors with relative resistance to ONC201 monotherapy.
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