Small-Molecule MYC Inhibitors Suppress Tumor Growth and Enhance Immunotherapy

Han, Huiying; Jain, Atul D.; Truica, Mihai I.; Izquierdo-Ferrer, Javier; Anker, Jonathan F.; Lysy, Barbara; Sagar, Vinay; Luan, Yi; Chalmers, Zachary R.; Unno, Kenji; Mok, Hanlin; Vatapalli, Rajita; Yoo, Young A.; Rodríguez, Yara; Kandela, Irawati; Parker, J. Brandon; Chakravarti, Debabrata; Mishra, Rama K.; Schiltz, Gary E.; Abdulkadir, Sarki A.

doi:10.1016/j.ccell.2019.10.001

Cited by 272 publications

(277 citation statements)

References 69 publications

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“…In future, we will test whether inhibition of USP1 in enzalutamide‐resistant cells could promote the PC cell response to enzalutamide. Although c‐Myc has been considered an undruggable target, potential c‐Myc small molecule inhibitors were recently developed 45 . Our findings suggest it would be better to test the possibility of c‐Myc inhibitor and USP1 inhibitor for the treatment of PC.…”

Section: Discussionmentioning

confidence: 91%

RETRACTED: Targeting USP1‐dependent KDM4A protein stability as a potential prostate cancer therapy

et al. 2020

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Abbreviations: AR, androgen receptor; ARE, androgen-responsive element; DUB, deubiquitinating enzyme; H3K9, histone H3 on lysine 9; H3K36, histone H3 on lysine 36; HA-ub, HA-tagged ubiquitin; IB, immunoblot; IHC, immunohistochemistry; IP, immunoprecipitation; KDM4A, lysine-specific demethylase 4A; PC, prostate cancer; PTEN, phosphatase and tensin homolog; qPCR, quantitative PCR. AbstractThe histone demethylase lysine-specific demethylase 4A (KDM4A) is reported to be overexpressed and plays a vital in multiple cancers through controlling gene expression by epigenetic regulation of H3K9 or H3K36 methylation marks. However, the biological role and mechanism of KDM4A in prostate cancer (PC) remain unclear.Herein, we reported KDM4A expression was upregulation in phosphatase and tensin homolog knockout mouse prostate tissue. Depletion of KDM4A in PC cells inhibited their proliferation and survival in vivo and vitro. Further studies reveal that USP1 is a deubiquitinase that regulates KDM4A K48-linked deubiquitin and stability.Interestingly, we found c-Myc was a key downstream effector of the USP1-KDM4A/ androgen receptor axis in driving PC cell proliferation. Notably, upregulation of KDM4A expression with high USP1 expression was observed in most prostate tumors and inhibition of USP1 promotes PC cells response to therapeutic agent enzalutamide. Our studies propose USP1 could be an anticancer therapeutic target in PC.

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Section: Discussionmentioning

confidence: 91%

RETRACTED: Targeting USP1‐dependent KDM4A protein stability as a potential prostate cancer therapy

et al. 2020

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“…This range is several orders of magnitude lower than the tested CPPs, which require micromolar doses to be effective. A recent study has reported small molecules able to inhibit Myc/Max interaction, which also require low micromolar range 31 . This significant difference could stem from a combination of at least two factors.…”

Section: Discussionmentioning

confidence: 99%

Targeting c-Myc with a novel Peptide Nuclear Delivery Device

Ting

Chaumet

Bard

2020

Preprint

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Biologics such as peptides and antibodies are a well-established class of therapeutics.However, their intracellular delivery remains problematic. In particular, methods to efficiently inhibit intra-nuclear targets are lacking. We previously described that Pseudomonas Exotoxin A reaches the nucleoplasm via the endosomes-to-nucleus trafficking pathway. Here, we show that a non-toxic truncated form of PE can be coupled to peptides and efficiently reach the nucleoplasm. It can be used as a Peptide Nuclear Delivery Device (PNDD) to deliver polypeptidic cargos as large as Glutathione-S-transferase (GST) to the nucleus. PNDD1 is a fusion of PNDD to the c-myc inhibitor peptide H1. PNDD1 is able to inhibit c-Myc dependent transcription at nanomolar concentration. In contrast, H1 fused to various cell-penetrating peptides are active only in the micromolar range. PNDD1 attenuates cell proliferation and induces cell death in various tumor cell lines. In particular, several patient-derived Diffuse Large B-Cell Lymphomas cell lines die after exposure to PNDD1, while normal B-cells survive. Altogether, our data indicate that PNDD is a powerful tool to bring active cargo to the nucleus and PNDD1 could be the basis of a new therapy against lymphoma.

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“…MYC may have a dual role in cancer progression, promoting both chromosomal instability and direct or indirect suppression of STING-mediated immune responses, resulting in an immunosuppressed microenvironment. The use of novel MYC inhibitors has been shown to increase immune infiltration in preclinical models although the mechanisms driving this infiltrate have not yet been described, and may be STING related 48 . Combining MYC inhibition and STING activation requires further preclinical study and could be a therapeutic approach in pnSTING low cases.…”

Section: Discussionmentioning

confidence: 99%

The clinical and molecular significance associated with STING signaling in estrogen receptor-positive early breast cancer

Parkes

Humphries

Gilmore

et al. 2020

Preprint

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STING signaling in cancer is a crucial component of response to immunotherapy and other anti-cancer treatments. Conversely, STING signaling can promote tumor invasion and metastasis. Currently, there is no robust method of measuring STING activation in cancer. Here, we describe an immunohistochemistry-based assay with digital pathology assessment of STING in tumor cells. Using this novel approach, we identify perinuclear-localized expression of STING (pnSTING) in estrogen receptor-positive (ER+) breast cancer as an independent predictor of good prognosis, associated with immune cell infiltration and upregulation of immune checkpoints. Tumors with low pnSTING are immunosuppressed with increased infiltration of “M2” -polarised macrophages. In ER-disease, pnSTING does not have a significant prognostic role, and STING appears to be uncoupled from interferon responses. Importantly, a gene signature defining low pnSTING expression in ER+ disease is predictive of poor prognosis in independent datasets. Low pnSTING is associated with chromosomal instability, MYC amplification and mTOR signaling, suggesting novel therapeutic approaches for this subgroup.

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Small-Molecule MYC Inhibitors Suppress Tumor Growth and Enhance Immunotherapy

Cited by 272 publications

References 69 publications

RETRACTED: Targeting USP1‐dependent KDM4A protein stability as a potential prostate cancer therapy

RETRACTED: Targeting USP1‐dependent KDM4A protein stability as a potential prostate cancer therapy

Targeting c-Myc with a novel Peptide Nuclear Delivery Device

The clinical and molecular significance associated with STING signaling in estrogen receptor-positive early breast cancer

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