Identification of TRAIL-inducing compounds highlights small molecule ONC201/TIC10 as a unique anti-cancer agent that activates the TRAIL pathway

Allen, Joshua E.; Krigsfeld, Gabriel; Patel, Luv; Mayes, Patrick A.; Dicker, David T.; Wu, Gen Sheng; El‐Deiry, Wafik S.

doi:10.1186/s12943-015-0346-9

Cited by 73 publications

(80 citation statements)

References 33 publications

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“…The compound was identified as a candidate anti-cancer lead compound in a luciferase reporter screen for small molecule p53-independent inducers of TNF-related apoptosis-inducing ligand (TRAIL) gene transcription in (TRAIL-resistant) bax-null HCT116 human colorectal cancer (CRC) cells [1, 2]. As a key effector of the immune-surveillance of cancer, TRAIL is a protein conditionally expressed on the surface of immune cells that triggers apoptosis in proximal tumor cells while not harming normal host cells [3].…”

Section: Discovery Of Onc201mentioning

confidence: 99%

Discovery and clinical introduction of first-in-class imipridone ONC201

et al. 2016

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ONC201 is the founding member of a novel class of anti-cancer compounds called imipridones that is currently in Phase II clinical trials in multiple advanced cancers. Since the discovery of ONC201 as a p53-independent inducer of TRAIL gene transcription, preclinical studies have determined that ONC201 has anti-proliferative and pro-apoptotic effects against a broad range of tumor cells but not normal cells. The mechanism of action of ONC201 involves engagement of PERK-independent activation of the integrated stress response, leading to tumor upregulation of DR5 and dual Akt/ERK inactivation, and consequent Foxo3a activation leading to upregulation of the death ligand TRAIL. ONC201 is orally active with infrequent dosing in animals models, causes sustained pharmacodynamic effects, and is not genotoxic. The first-in-human clinical trial of ONC201 in advanced aggressive refractory solid tumors confirmed that ONC201 is exceptionally well-tolerated and established the recommended phase II dose of 625 mg administered orally every three weeks defined by drug exposure comparable to efficacious levels in preclinical models. Clinical trials are evaluating the single agent efficacy of ONC201 in multiple solid tumors and hematological malignancies and exploring alternative dosing regimens. In addition, chemical analogs that have shown promise in other oncology indications are in pre-clinical development. In summary, the imipridone family that comprises ONC201 and its chemical analogs represent a new class of anti-cancer therapy with a unique mechanism of action being translated in ongoing clinical trials.

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Section: Discovery Of Onc201mentioning

confidence: 99%

Discovery and clinical introduction of first-in-class imipridone ONC201

et al. 2016

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“…To confirm that ONC201 was toxic to leukemic stem cells (LSCs), defined as primary AML cells that can engraft in immunodeficient mice, we recovered unfractionated LSC-containing populations of AML cells [t(9;11)(p22; q23), CEBPA and ATM mutant] from secondarily engrafted mice and cultured them in vitro for 48 hours, with or without ONC201. For both groups, the same number of washed, trypan blue–negative (viable) cells was then retransplanted.…”

Section: Resultsmentioning

confidence: 99%

“…ONC201 (previously referred to as TIC10) is a first-in-class small molecule that was identified in a high-throughput small-molecule library screen as potent inducer of p53-independent apoptosis in tumor cells, with a remarkable safety profile (11, 12). In solid tumors, ONC201 caused late-stage induction of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) death receptor 5 (DR5) and promoted the transcription of the TRAIL gene, the latter through activation of the transcription factor FOXO3a caused by late-stage inactivation of signaling by the kinases AKT and MAPK (mitogen-activated protein kinase) (12).…”

Section: Introductionmentioning

confidence: 99%

ATF4 induction through an atypical integrated stress response to ONC201 triggers p53-independent apoptosis in hematological malignancies

et al. 2016

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The clinical challenge posed by p53 abnormalities in hematological malignancies requires therapeutic strategies other than standard genotoxic chemotherapies. ONC201 is a first-in-class small molecule that activates p53-independent apoptosis, has a benign safety profile, and is in early clinical trials. We found that ONC201 caused p53-independent apoptosis and cell cycle arrest in cell lines and in mantle cell lymphoma (MCL) and acute myeloid leukemia (AML) samples from patients; these included samples from patients with genetic abnormalities associated with poor prognosis or cells that had developed resistance to the nongenotoxic agents ibrutinib and bortezomib. Moreover, ONC201 caused apoptosis in stem and progenitor AML cells and abrogated the engraftment of leukemic stem cells in mice while sparing normal bone marrow cells. ONC201 caused changes in gene expression similar to those caused by the unfolded protein response (UPR) and integrated stress responses (ISRs), which increase the translation of the transcription factor ATF4 through an increase in the phosphorylation of the translation initiation factor eIF2α. However, unlike the UPR and ISR, the increase in ATF4 abundance in ONC201-treated hematopoietic cells promoted apoptosis and did not depend on increased phosphorylation of eIF2α. ONC201 also inhibited mammalian target of rapamycin complex 1 (mTORC1) signaling, likely through ATF4-mediated induction of the mTORC1 inhibitor DDIT4. Overexpression of BCL-2 protected against ONC201-induced apoptosis, and the combination of ONC201 and the BCL-2 antagonist ABT-199 synergistically increased apoptosis. Thus, our results suggest that by inducing an atypical ISR and p53-independent apoptosis, ONC201 has clinical potential in hematological malignancies.

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“…TRAIL has been of interest as a cancer therapeutic due to its ability to induce cell death in cancer cells while sparing normal cells [2], but many breast cancers show resistance [8]. ONC201 was initially identified as a small molecule inducer of the TRAIL pathway [3] and cell death.…”

Section: Discussionmentioning

confidence: 99%

“…ONC201 was originally identified as a p53-independent transcriptional inducer of TNF-related apoptosis inducing ligand (TRAIL) [2,3]. TRAIL is a protein that binds to death receptors DR4 and DR5, inducing cell death in tumor cells but not normal cells [4].…”

Section: Introductionmentioning

confidence: 99%

ONC201 Demonstrates Antitumor Effects in Both Triple-Negative and Non–Triple-Negative Breast Cancers through TRAIL-Dependent and TRAIL-Independent Mechanisms

Ralff

Kline

Küçükkase

et al. 2017

Molecular Cancer Therapeutics

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Breast cancer is a major cause of cancer-related death. 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 succumb to ONC201-induced cell death. In 2/8 TNBC cell lines, ONC201 treatment induces caspase-8 cleavage and cell death that is blocked by TRAIL-neutralizing antibody RIK2. The pro-apoptotic 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 anti-proliferative 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 anti-proliferative 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) show PARP cleavage. In these cells, cell death induced by ONC201 is TRAIL-independent. Our data demonstrate that ONC201 has potent anti-proliferative and pro-apoptotic effects in a broad range of breast cancer subtypes, through TRAIL-dependent and TRAIL-independent mechanisms. These findings develop a pre-clinical rationale for developing ONC201 as a single agent and/or in combination with approved therapies in breast cancer.

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Identification of TRAIL-inducing compounds highlights small molecule ONC201/TIC10 as a unique anti-cancer agent that activates the TRAIL pathway

Cited by 73 publications

References 33 publications

Discovery and clinical introduction of first-in-class imipridone ONC201

Discovery and clinical introduction of first-in-class imipridone ONC201

ATF4 induction through an atypical integrated stress response to ONC201 triggers p53-independent apoptosis in hematological malignancies

ONC201 Demonstrates Antitumor Effects in Both Triple-Negative and Non–Triple-Negative Breast Cancers through TRAIL-Dependent and TRAIL-Independent Mechanisms

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