mTOR inhibition sensitizes ONC201-induced anti-colorectal cancer cell activity

Jin, Zhe-zhu; Wang, Wei; Fang, Dilong; Jin, Yongjun

doi:10.1016/j.bbrc.2016.08.126

Cited by 18 publications

(17 citation statements)

References 32 publications

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“…The mTOR kinase inhibitor AZD-8055 was shown to synergize with ONC201 in CRC, potentiating its antiproliferative activity and enhancing its cytotoxicity in CRC cells via TRAIL induction. Moreover, the combination led to inactivation of Akt and mTOR activation in vitro [57] .…”

Section: Onc201 Preclinical Efficacy and Safetymentioning

confidence: 96%

“…Such effects were observed both in vitro and in vivo through the use of colonosphere formation assays and subcutaneous CRC xenografts in mice [37] , [38] . Resistance to ONC201 treatment in CRC can arise through the overexpression or mutation of DRD5 or hyperactivation of mTOR [26] , [57] .…”

Section: Onc201 Preclinical Efficacy and Safetymentioning

confidence: 99%

“…mTOR signaling can serve as an innate resistance mechanism to ONC201 in CRC, prompting exploration of mTOR inhibitor combination therapy [57] , [60] . The mTOR kinase inhibitor AZD-8055 was shown to synergize with ONC201 in CRC, potentiating its antiproliferative activity and enhancing its cytotoxicity in CRC cells via TRAIL induction.…”

Section: Onc201 Preclinical Efficacy and Safetymentioning

confidence: 99%

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ONC201 and imipridones: Anti-cancer compounds with clinical efficacy

et al. 2020

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ONC201 was originally discovered as TNF-Related Apoptosis Inducing Ligand (TRAIL)-inducing compound TIC10. ONC201 appears to act as a selective antagonist of the G protein coupled receptor (GPCR) dopamine receptor D2 (DRD2), and as an allosteric agonist of mitochondrial protease caseinolytic protease P (ClpP). Downstream of target engagement, ONC201 activates the ATF4/CHOP-mediated integrated stress response leading to TRAIL/Death Receptor 5 (DR5) activation, inhibits oxidative phosphorylation via c-myc, and inactivates Akt/ERK signaling in tumor cells. This typically results in DR5/TRAIL-mediated apoptosis of tumor cells; however, DR5/TRAIL-independent apoptosis, cell cycle arrest, or antiproliferative effects also occur. The effects of ONC201 extend beyond bulk tumor cells to include cancer stem cells, cancer associated fibroblasts and immune cells within the tumor microenvironment that can contribute to its efficacy. ONC201 is orally administered, crosses the intact blood brain barrier, and is under evaluation in clinical trials in patients with advanced solid tumors and hematological malignancies. ONC201 has single agent clinical activity in tumor types that are enriched for DRD2 and/or ClpP expression including specific subtypes of high-grade glioma, endometrial cancer, prostate cancer, mantle cell lymphoma, and adrenal tumors. Synergy with radiation, chemotherapy, targeted therapy and immune-checkpoint agents has been identified in preclinical models and is being evaluated in clinical trials. Structure-activity relationships based on the core pharmacophore of ONC201, termed the imipridone scaffold, revealed novel potent compounds that are being developed. Imipridones represent a novel approach to therapeutically target previously undruggable GPCRs, ClpP, and innate immune pathways in oncology.

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Section: Onc201 Preclinical Efficacy and Safetymentioning

confidence: 96%

Section: Onc201 Preclinical Efficacy and Safetymentioning

confidence: 99%

Section: Onc201 Preclinical Efficacy and Safetymentioning

confidence: 99%

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ONC201 and imipridones: Anti-cancer compounds with clinical efficacy

et al. 2020

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“…We also recently demonstrated potent antitumor effects on colorectal cancers initiated by cancer stem/progenitor cells (CSCs) (7). In vivo, first-in-class small molecule ONC201 exhibits a broad spectrum of anticancer activity, a wide safety margin, robust stability, aqueous solubility, blood-brain barrier penetration, and favorable pharmacokinetics (1)(2)(3)(4)(5)(7)(8)(9)(10)(11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

Dose intensification of TRAIL-inducing ONC201 inhibits metastasis and promotes intratumoral NK cell recruitment

Wagner¹,

Kline²,

Zhou³

et al. 2018

Journal of Clinical Investigation

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ONC201 is a first-in-class, orally active antitumor agent that upregulates cytotoxic TRAIL pathway signaling in cancer cells. ONC201 has demonstrated safety and preliminary efficacy in a first-in-human trial in which patients were dosed every 3 weeks. We hypothesized that dose intensification of ONC201 may impact antitumor efficacy. We discovered that ONC201 exerts dose- and schedule-dependent effects on tumor progression and cell death signaling in vivo. With dose intensification, we note a potent anti-metastasis effect and inhibition of cancer cell migration and invasion. Our preclinical results prompted a change in ONC201 dosing in all open clinical trials. We observed accumulation of activated NK+ and CD3+ cells within ONC201-treated tumors and that NK cell depletion inhibits ONC201 efficacy in vivo, including against TRAIL/ONC201-resistant Bax-/- tumors. Immunocompetent NCR1-GFP mice, in which NK cells express GFP, demonstrated GFP+ NK cell infiltration of syngeneic MC38 colorectal tumors. Activation of primary human NK cells and increased degranulation occurred in response to ONC201. Coculture experiments identified a role for TRAIL in human NK-mediated antitumor cytotoxicity. Preclinical results indicate the potential utility for ONC201 plus anti-PD-1 therapy. We observed an increase in activated TRAIL-secreting NK cells in the peripheral blood of patients after ONC201 treatment. The results offer what we believe to be a unique pathway of immune stimulation for cancer therapy.

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“…By means of bromodeoxyuridine (BrdU) labelling experiments the authors also confirmed that the proliferation of the cells was inhibited by ONC201 and, as a response to the treatment with this impiridone, the early cell cycle arrest caused a significant decrease in a number of viable cells within 48 h, even including those (e.g., A-549 and SNV-449) that did not undergo apoptosis [ 24 ]. Preclinical studies have demonstrated its potency as an exceptionally promising apoptotic anticancer agent having pronounced activity against a large variety of cancer cell lines (including e.g., PANC-1, HCT116, MDA-MB-23, U87, HFF, MRC5, and WI-38) [ 28 , 29 , 30 , 31 ]. Moreover, in phase II clinical trials this compound has proved to be beneficial in the treatment of patients with a wide range of advanced malignances [ 32 ].…”

Section: Introductionmentioning

confidence: 99%

Ferrocene-Containing Impiridone (ONC201) Hybrids: Synthesis, DFT Modelling, In Vitro Evaluation, and Structure–Activity Relationships

et al. 2018

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Inspired by the well-established clinical evidence about the interplay between apoptotic TRAIL (tumour necrosis factor-related apoptosis-inducing ligand) mechanism and reactive oxygen species (ROS)-mediated oxidative stress, a set of novel ONC201 hybrids containing the impiridone core and one or two differently positioned ferrocenylalkyl groups were synthesised in our present work. These two types of residues have been implicated in the aforementioned mechanisms associated with cytotoxic activity. A straightforward, primary amine-based synthetic approach was used allowing the introduction of a variety of N-substituents into the two opposite regions of the heterocyclic skeleton. Reference model compounds with benzyl and halogenated benzyl groups were also synthesised and tested. The in vitro assays of the novel impiridones on five malignant cell lines disclosed characteristic structure-activity relationship (SAR) featuring significant substituent-dependent activity and cell-selectivity. A possible contribution of ROS-mechanism to the cytotoxicity of the novel metallocenes was suggested by density functional theory (DFT)studies on simplified models. Accordingly, unlike the mono-ferrocenylalkyl-substituted products, the compounds containing two ferrocenylalkyl substituents in the opposite regions of the impiridone core display a much more pronounced long-term cytotoxic effect against A-2058 cell line than do the organic impiridones including ONC201 and ONC212. Furthermore, the prepared bis-metallocene derivatives also present substantial activity against COLO-205- and EBC-1 cell lines.

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mTOR inhibition sensitizes ONC201-induced anti-colorectal cancer cell activity

Cited by 18 publications

References 32 publications

ONC201 and imipridones: Anti-cancer compounds with clinical efficacy

ONC201 and imipridones: Anti-cancer compounds with clinical efficacy

Dose intensification of TRAIL-inducing ONC201 inhibits metastasis and promotes intratumoral NK cell recruitment

Ferrocene-Containing Impiridone (ONC201) Hybrids: Synthesis, DFT Modelling, In Vitro Evaluation, and Structure–Activity Relationships

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