ONC201 kills solid tumor cells by triggering an integrated stress response dependent on ATF4 activation by specific eIF2α kinases

Kline, Christina Leah B.; Heuvel, A. Pieter J. van den; Allen, Joshua E.; Prabhu, Varun V.; Dicker, David T.; El‐Deiry, Wafik S.

doi:10.1126/scisignal.aac4374

Cited by 147 publications

(217 citation statements)

References 45 publications

(68 reference statements)

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“…On the other hand, we showed that ATF4 and CHOP were induced by ONC201, and that knockdown of ATF4 attenuated ONC201-induced growth inhibition of MDA231 cells, indicating that ATF4-mediated ER stress is involved in ONC201-induced anticancer activity. These results are consistent with two recent studies in other cancer types showing that the activation of ATF4-mediated ER stress is required for ONC201-induced antitumor activity [39, 40]. Thus, we conclude that ONC201 activates two ER stress pathways, but the activation of ATF4-mediated ER stress is responsible for ONC201-induced antitumor activity in TNBC cells.…”

Section: Discussionsupporting

confidence: 93%

ONC201 activates ER stress to inhibit the growth of triple-negative breast cancer cells

Kho

Gajan

et al. 2017

Oncotarget

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ONC201 was previously identified as a first-in-class antitumor agent and small-molecule inducer of the TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) gene that induces apoptosis in cancer cells. ONC201 has a safety profile and is currently in phase II clinical trials for the treatment of various malignancies. In the current study, we examine the effect of ONC201 on triple-negative breast cancer cells (TNBC), a subtype of breast cancer that is sensitive to TRAIL. We find that ONC201 inhibits the growth of TNBC cells including TNBC cells that have developed acquired TRAIL resistance. However, TNBC cells that have developed acquired ONC201 resistance are cross-resistant to TRAIL. Mechanistically, ONC201 triggers an integrated stress response (ISR) involving the activation of the transcription factor ATF4. Knockdown of ATF4 impairs ONC201-induced apoptosis of TNBC cells. Importantly, the activation of ATF4 is compromised in ONC201-resistant TNBC cells. Thus, our results indicate that ONC201 induces an ISR to cause TNBC cell death and suggest that TNBC patients may benefit from ONC201-based therapies.

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Section: Discussionsupporting

confidence: 93%

ONC201 activates ER stress to inhibit the growth of triple-negative breast cancer cells

Kho

Gajan

et al. 2017

Oncotarget

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“…The induction of an ISR reported here is also operational in solid tumors [see Kline et al (64)]. Ongoing phase 1/2 clinical trials of ONC201 (NCT02038699) are enrolling patients with advanced solid tumors, and phase 1/2 studies in AML and lymphomas have opened at MD Anderson Cancer Center (NCT02392572), providing the opportunity to corroborate the mechanism of action and other effects identified here in translational studies.…”

Section: Discussionsupporting

confidence: 52%

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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“…1,2 Similarly, ONC212 and ONC206 significantly induced Sub-G1 apoptotic cells and/or cell cycle arrest. Interestingly, ONC212 and ONC206 did not induce cell cycle arrest in a colorectal cell line with acquired ONC201-resistance (RKO-ONC201 resistant 2 ), suggesting cross-resistance between the compounds.…”

Section: Generation Of Onc201 Chemical Derivatives Yielded Several Immentioning

confidence: 95%

“…[1][2][3] When activated by the ligand TRAIL, DR5 triggers the extrinsic cell death pathway that selectively induces apoptosis in a variety of tumor and transformed cells, including cancer stem cells, without affecting normal cells. 4,5 The unique ability of ONC201 to induced TRAIL-based signaling to induce apoptosis in cancer cells and not normal cells leads to a wide therapeutic index and favorable characteristics as an anti-cancer therapeutic.…”

Section: Introductionmentioning

confidence: 99%

“…4,5 The unique ability of ONC201 to induced TRAIL-based signaling to induce apoptosis in cancer cells and not normal cells leads to a wide therapeutic index and favorable characteristics as an anti-cancer therapeutic. [1][2][3]6,7 The TRAIL pathway is a powerful effector cytokine in the innate host immune response that suppresses tumor development, progression and metastasis. Early results from a Phase I clinical trial in advanced solid tumors demonstrated that ONC201 has a therapeutic PK profile, exceptional safety, induction of pharmacodynamics (PD) markers, and preliminary evidence of efficacy in various types of cancers.…”

Section: Introductionmentioning

confidence: 99%

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Preclinical evaluation of the imipridone family, analogs of clinical stage anti-cancer small molecule ONC201, reveals potent anti-cancer effects of ONC212

et al. 2017

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Anti-cancer small molecule ONC201 upregulates the integrated stress response (ISR) and acts as a dual inactivator of Akt/ERK, leading to TRAIL gene activation. ONC201 is under investigation in multiple clinical trials to treat patients with cancer. Given the unique imipridone core chemical structure of ONC201, we synthesized a series of analogs to identify additional compounds with distinct therapeutic properties. Several imipridones with a broad range of in vitro potencies were identified in an exploration of chemical derivatives. Based on in vitro potency in human cancer cell lines and lack of toxicity to normal human fibroblasts, imipridones ONC206 and ONC212 were prioritized for further study. Both analogs inhibited colony formation, and induced apoptosis and downstream signaling that involves the integrated stress response and Akt/ERK, similar to ONC201. Compared to ONC201, ONC206 demonstrated improved inhibition of cell migration while ONC212 exhibited rapid kinetics of activity. ONC212 was further tested in >1000 human cancer cell lines in vitro and evaluated for safety and anti-tumor efficacy in vivo. ONC212 exhibited broad-spectrum efficacy at nanomolar concentrations across solid tumors and hematological malignancies. Skin cancer emerged as a tumor type with improved efficacy relative to ONC201. Orally administered ONC212 displayed potent anti-tumor effects in vivo, a broad therapeutic window and a favorable PK profile. ONC212 was efficacious in vivo in BRAF V600E melanoma models that are less sensitive to ONC201. Based on these findings, ONC212 warrants further development as a drug candidate. It is clear that therapeutic utility extends beyond ONC201 to include additional imipridones.

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ONC201 kills solid tumor cells by triggering an integrated stress response dependent on ATF4 activation by specific eIF2α kinases

Cited by 147 publications

References 45 publications

ONC201 activates ER stress to inhibit the growth of triple-negative breast cancer cells

ONC201 activates ER stress to inhibit the growth of triple-negative breast cancer cells

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

Preclinical evaluation of the imipridone family, analogs of clinical stage anti-cancer small molecule ONC201, reveals potent anti-cancer effects of ONC212

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