The ubiquitin-activating enzyme, UBA1, as a novel therapeutic target for AML

Barghout, Samir H.; Schimmer, Aaron D.

doi:10.18632/oncotarget.26153

Cited by 13 publications

(13 citation statements)

References 10 publications

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“…Administration of TAK-243 to mouse models of PDAC at doses that recapitulate the biological effects (activation of the UPR and apoptosis) observed in cultured cells, led to a tumor growth delay but did not exhibit any obvious normal tissue toxicity. This is in agreement with similar studies in AML [ 43 ], myeloma [ 35 ], B-cell lymphoma [ 18 ], squamous cell carcinoma, among others [ 44 ]. In agreement with the reported cellular response to TAK-243 in each of the above disease sites, our findings demonstrate that inhibition of protein ubiquitination leads to a dramatic induction of ER stress and activation of the UPR signaling pathway.…”

Section: Discussionsupporting

confidence: 93%

UAE1 inhibition mediates the unfolded protein response, DNA damage and caspase-dependent cell death in pancreatic cancer

Liu

Awadia

Delaney

et al. 2020

Translational Oncology

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The Unfolded Protein Response (UPR) plays a key role in the adaptive response to loss of protein homeostasis within the endoplasmic reticulum (ER). The UPR has an adaptive function in protein homeostasis, however, sustained activation of the UPR due to hypoxia, nutrient deprivation, and increased demand for protein synthesis, alters the UPR program such that additional perturbation of ER homeostasis activates a pro-apoptotic program. Since ubiquitination followed by proteasomal degradation of misfolded proteins within the ER is a central mechanism for restoration of ER homeostasis, inhibitors of this pathway have proven to be valuable anti-cancer therapeutics. Ubiquitin activating enzyme 1(UAE1), activates ubiquitin for transfer to target proteins for proteasomal degradation in conjunction with E2 and E3 enzymes. Inhibition of UAE1 activity in response to TAK-243, leads to an accumulation of misfolded proteins within the ER, thereby aggravating ER stress, leading to DNA damage and arrest of cells in the G2/M phase of the cell cycle. Persistent drug treatment mediates a robust induction of apoptosis following a transient cell cycle arrest. These biological effects of TAK-243 were recapitulated in mouse models of PDAC demonstrating antitumor activity at a dose and schedule that did not exhibit obvious normal tissue toxicity. In vitro as well as studies in mouse models failed to show enhanced efficacy when TAK-243 was combined with ionizing radiation or gemcitabine, providing an impetus for future studies to identify agents that synergize with this class of agents for improved tumor control in PDAC. Significance The UAE1 inhibitor TAK-243, mediates activation of the unfolded protein response, accumulation of DNA breaks and apoptosis, providing a rationale for the use as a safe and efficacious anti-cancer therapeutic for PDAC.

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Section: Discussionsupporting

confidence: 93%

UAE1 inhibition mediates the unfolded protein response, DNA damage and caspase-dependent cell death in pancreatic cancer

Liu

Awadia

Delaney

et al. 2020

Translational Oncology

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“…UBA1 was also reported by others to serve as a therapeutic target in cancer ( 8 ). Accordingly, we evaluated the selective UBA1 inhibitor, TAK-243, in preclinical models of AML and found that it displayed potent antileukemic activity in vitro and in vivo ( 9 , 10 ). Similar findings have also been reported with TAK-243 in solid tumors and other hematologic malignancies ( 2 , 11 – 13 ).…”

Section: Introductionmentioning

confidence: 99%

A genome-wide CRISPR/Cas9 screen in acute myeloid leukemia cells identifies regulators of TAK-243 sensitivity

et al. 2021

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TAK-243 is a first-in-class inhibitor of ubiquitin-like modifier activating enzyme 1 that catalyzes ubiquitin activation, the first step in the ubiquitylation cascade. Based on its preclinical efficacy and tolerability, TAK-243 has been advanced to phase I clinical trials in advanced malignancies. Nonetheless, the determinants of TAK-243 sensitivity remain largely unknown. Here, we conducted a genome-wide CRISPR/Cas9 knockout screen in acute myeloid leukemia (AML) cells in the presence of TAK-243 to identify genes essential for TAK-243 action. We identified BEN domain-containing protein 3 ( BEND3 ), a transcriptional repressor and a regulator of chromatin organization, as the top gene whose knockout confers resistance to TAK-243 in vitro and in vivo. Knockout of BEND3 dampened TAK-243 effects on ubiquitylation, proteotoxic stress, and DNA damage response. BEND3 knockout upregulated the ATP-binding cassette efflux transporter breast cancer resistance protein (BCRP; ABCG2) and reduced the intracellular levelsof TAK-243. TAK-243 sensitivity correlated with BCRP expression in cancer cell lines of different origins. Moreover, chemical inhibition and genetic knockdown of BCRP sensitized intrinsically resistant high-BCRP cells to TAK-243. Thus, our data demonstrate that BEND3 regulates the expression of BCRP for which TAK-243 is a substrate. Moreover, BCRP expression could serve as a predictor of TAK-243 sensitivity.

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“…The drug binds free ubiquitin to form a TAK-243-ubiquitin adduct inhibiting UBA1 (22). Consequently, TAK-243 impairs cellular ubiquitin conjugation resulting in proteotoxic stress and ultimately cancer cell death (23)(24)(25)(26)(27)(28)(29). Here we report that TAK-243 is more cytotoxic in the absence of SLFN11 in preclinical cancer cell line models.…”

Section: Tak-243 (Initial Designation Mln7243mentioning

confidence: 72%

SLFN11 Inactivation Induces Proteotoxic Stress and Sensitizes Cancer Cells to Ubiquitin Activating Enzyme Inhibitor TAK-243

Murai

et al. 2021

Cancer Research

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The ubiquitin-activating enzyme, UBA1, as a novel therapeutic target for AML

Cited by 13 publications

References 10 publications

UAE1 inhibition mediates the unfolded protein response, DNA damage and caspase-dependent cell death in pancreatic cancer

UAE1 inhibition mediates the unfolded protein response, DNA damage and caspase-dependent cell death in pancreatic cancer

A genome-wide CRISPR/Cas9 screen in acute myeloid leukemia cells identifies regulators of TAK-243 sensitivity

SLFN11 Inactivation Induces Proteotoxic Stress and Sensitizes Cancer Cells to Ubiquitin Activating Enzyme Inhibitor TAK-243

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