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|Ref Type||Journal Article|
|Authors||Ishizawa J, Kojima K, Chachad D, Ruvolo P, Ruvolo V, Jacamo RO, Borthakur G, Mu H, Zeng Z, Tabe Y, Allen JE, Wang Z, Ma W, Lee HC, Orlowski R, Sarbassov dos D, Lorenzi PL, Huang X, Neelapu SS, McDonnell T, Miranda RN, Wang M, Kantarjian H, Konopleva M, Davis RE, Andreeff M|
|Title||ATF4 induction through an atypical integrated stress response to ONC201 triggers p53-independent apoptosis in hematological malignancies.|
|Date||2016 Feb 16|
|Abstract Text||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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||mantle cell lymphoma||not applicable||ONC201||Preclinical - Patient cell culture||Actionable||In a preclinical study, ONC201 induced apoptosis and decreased viability of mantle cell lymphoma (MCL) cell lines in culture and demonstrated cytotoxicity in primary MCL samples in culture (PMID: 26884599).||26884599 detail...|
|Unknown unknown||multiple myeloma||not applicable||ONC201||Preclinical - Cell culture||Actionable||In a preclinical study, a Velcade (bortezomib)-resistant multiple myeloma cell line demonstrated sensitivity to ONC201 in culture (PMID: 26884599).||26884599|
|Unknown unknown||mantle cell lymphoma||not applicable||ONC201 + Venetoclax||Preclinical - Cell culture||Actionable||In a preclinical study, the combination of ONC201and Venclexta (venetoclax) demonstrated synergy in a mantle cell lymphoma cell line in culture, resulting in increased induction of apoptosis (PMID: 26884599).||26884599|
|Unknown unknown||acute myeloid leukemia||not applicable||ONC201||Preclinical - Pdx & cell culture||Actionable||In a preclinical study, ONC201 treatment induced ATF4 expression and apoptosis in acute myeloid leukemia (AML) cell lines in culture, independent of Tp53 status, and was toxic to AML primary samples in culture, resulting in decreased engraftment in xenograft models (PMID: 26884599).||26884599|
|Unknown unknown||mantle cell lymphoma||not applicable||Ibrutinib + ONC201||Preclinical - Patient cell culture||Actionable||In a preclinical study, the combination of ONC201 and Imbruvica (ibrutinib) induced apoptosis in primary mantle cell lymphoma samples in culture, including Imbruvica (ibrutinib)-resistant samples, with greater efficacy than either agent alone (PMID: 26884599).||26884599|
|Unknown unknown||acute myeloid leukemia||not applicable||ONC201 + Venetoclax||Preclinical - Cell culture||Actionable||In a preclinical study, the combination of ONC201 and Venclexta (venetoclax) demonstrated synergy in acute myeloid leukemia cell lines in culture, resulting in increased induction of apoptosis (PMID: 26884599).||26884599|