Genetic and Pharmacological Screens Converge in Identifying FLIP, BCL2, and IAP Proteins as Key Regulators of Sensitivity to the TRAIL-Inducing Anticancer Agent ONC201/TIC10

Allen, Joshua E.; Prabhu, Varun V.; Talekar, Mala; Heuvel, A. Pieter J. van den; Lim, Bora; Dicker, David T.; Fritz, Jennifer L.; Beck, Adam; El‐Deiry, Wafik S.

doi:10.1158/0008-5472.can-14-2356

Cited by 42 publications

(44 citation statements)

References 18 publications

(23 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…27 This study investigated a subset of approved small molecules that were curated for NHL relevance. Our limited combinatorial study identified cytarabine as a synergistic combination with ONC201 in pediatric NHL.…”

Section: Discussionmentioning

confidence: 99%

“…We recently reported that ONC201 exhibits synergy with several approved targeted agents and chemotherapies that range from multikinase inhibitors, alkylating agents and inhibitors of DNA/ nucleoside synthesis. 27 We specifically examined the combinatorial efficacy of ONC201 with chemotherapies used to treat pediatric lymphoma (Fig. 4A).…”

Section: Onc201 Cooperates With Several Pediatric Lymphoma Chemotheramentioning

confidence: 99%

See 1 more Smart Citation

ONC201 induces cell death in pediatric non-Hodgkin's lymphoma cells

Talekar¹,

Allen

Dicker

et al. 2015

Cell Cycle

View full text Add to dashboard Cite

Abbreviations: TRAIL, TNF-related apoptosis-inducing ligand; DR5, death receptor 5; TNF, tumor necrosis family; NHL, non-Hodgkin's lymphoma.ONC201/TIC10 is a small molecule initially discovered by its ability to coordinately induce and activate the TRAIL pathway selectively in tumor cells and has recently entered clinical trials in adult advanced cancers. The anti-tumor activity of ONC201 has previously been demonstrated in several preclinical models of cancer, including refractory solid tumors and a transgenic lymphoma mouse model. Based on the need for new safe and effective therapies in pediatric non-Hodgkin's lymphoma (NHL) and the non-toxic preclinical profile of ONC201, we investigated the in vitro efficacy of ONC201 in non-Hodgkin's lymphoma (NHL) cell lines to evaluate its therapeutic potential for this disease. ONC201 caused a dose-dependent reduction in the cell viability of NHL cell lines that resulted from induction of apoptosis. As expected from prior observations, induction of TRAIL and its receptor DR5 was also observed in these cell lines. Furthermore, dual induction of TRAIL and DR5 appeared to drive the observed apoptosis and TRAIL expression was correlated linearly with sub-G1 DNA content, suggesting its potential role as a biomarker of tumor response to ONC201-treated lymphoma cells. We further investigated combinations of ONC201 with approved chemotherapeutic agents used to treat lymphoma. ONC201 exhibited synergy in combination with the anti-metabolic agent cytarabine in vitro, in addition to cooperating with other therapies. Together these findings indicate that ONC201 is an effective TRAIL pathway-inducer as a monoagent that can be combined with chemotherapy to enhance therapeutic responses in pediatric NHL.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Onc201 Cooperates With Several Pediatric Lymphoma Chemotheramentioning

confidence: 99%

ONC201 induces cell death in pediatric non-Hodgkin's lymphoma cells

Talekar¹,

Allen

Dicker

et al. 2015

Cell Cycle

View full text Add to dashboard Cite

show abstract

“…ONC201 has substantial antitumor activity in preclinical models in various advanced solid tumors with infrequent oral dosing and without toxicity in normal cells in culture and in vivo (12). Preclinical studies demonstrated broad synergism of ONC201 with established anticancer therapies, including the depletion of colorectal cancer stem cells (13, 14). …”

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Genetic and Pharmacological Screens Converge in Identifying FLIP, BCL2, and IAP Proteins as Key Regulators of Sensitivity to the TRAIL-Inducing Anticancer Agent ONC201/TIC10

Cited by 42 publications

References 18 publications

ONC201 induces cell death in pediatric non-Hodgkin's lymphoma cells

ONC201 induces cell death in pediatric non-Hodgkin's lymphoma cells

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

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

Contact Info

Product

Resources

About