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.
Highlights
Breast cancer is the most commonly diagnosed cancer and is the number three cause of cancer-related death in United States women
We previously showed that most breast cancer cells lines were resistant to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and did not undergo cell death following treatment with ONC201 [18]
Cell cycle profiling following propidium iodide staining indicates that the percent of non-triple negative breast cancer (TNBC) cells with subG1 DNA content does not increase from that observed in the vehicle control (Figure 1B, Supplementary Figure 1B)
Summary
Breast cancer is the most commonly diagnosed cancer and is the number three cause of cancer-related death in United States women. One promising therapeutic is ONC201, a compound being tested clinically in recurrent or refractory metastatic breast cancer (NCT03394027). ONC201 was initially identified as a tumor necrosis factor-related apoptosisinducing ligand (TRAIL) pathway inducer [1]. The potential of TRAIL to kill cancerous cells while leaving normal cells unharmed led to the development and clinical testing of TRAIL-based therapies such as recombinant human TRAIL (rhTRAIL; APO2L/TRAIL; dulanermin) and death receptor agonistic antibodies. These TRAIL-based therapies showed limited clinical efficacy, leading to investigation of alternative strategies to activate this potent pro-apoptotic pathway
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