Inhibition of c-Myc by 10058-F4 induces growth arrest and chemosensitivity in pancreatic ductal adenocarcinoma

Zhang, Meng; Fan, Haiyan; Li, Shengchao

doi:10.1016/j.biopha.2015.05.019

Cited by 32 publications

(24 citation statements)

References 23 publications

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“…However, MYC inhibition strategies have been developed based on interrupting protein–protein interactions with MAX to abolish MYC‐dependent transcriptional activity . As a proof of concept, we demonstrated that MYC inhibitors blocked FGF2‐induced cell proliferation in vitro in MCF‐7 and T47D cells, this inhibition occurred even at concentrations lower than those reported to block cell proliferation in other cell lines, underscoring the exquisite sensitivity of these models . For in vivo assays, we used the C4‐HI murine model in which we have already demonstrated that its hormone‐independent growth relies on stromal FGF2 .…”

Section: Discussionmentioning

confidence: 91%

FGF2 induces breast cancer growth through ligand‐independent activation and recruitment of ERα and PRBΔ4 isoform to MYC regulatory sequences

Giulianelli

Riggio

Guillardoy

et al. 2019

Intl Journal of Cancer

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Progression to hormone‐independent growth leading to endocrine therapy resistance occurs in a high proportion of patients with estrogen receptor alpha (ERα) and progesterone receptors (PR) positive breast cancer. We and others have previously shown that estrogen‐ and progestin‐induced tumor growth requires ERα and PR interaction at their target genes. Here, we show that fibroblast growth factor 2 (FGF2)‐induces cell proliferation and tumor growth through hormone‐independent ERα and PR activation and their interaction at the MYC enhancer and proximal promoter. MYC inhibitors, antiestrogens or antiprogestins reverted FGF2‐induced effects. LC–MS/MS identified 700 canonical proteins recruited to MYC regulatory sequences after FGF2 stimulation, 397 of which required active ERα (ERα‐dependent). We identified ERα‐dependent proteins regulating transcription that, after FGF2 treatment, were recruited to the enhancer as well as proteins involved in transcription initiation that were recruited to the proximal promoter. Also, among the ERα‐dependent and independent proteins detected at both sites, PR isoforms A and B as well as the novel protein product PRBΔ4 were found. PRBΔ4 lacks the hormone‐binding domain and was able to induce reporter gene expression from estrogen‐regulated elements and to increase cell proliferation when cells were stimulated with FGF2 but not by progestins. Analysis of the Cancer Genome Atlas data set revealed that PRBΔ4 expression is associated with worse overall survival in luminal breast cancer patients. This discovery provides a new mechanism by which growth factor signaling can engage nonclassical hormone receptor isoforms such as PRBΔ4, which interacts with growth‐factor activated ERα and PR to stimulate MYC gene expression and hence progression to endocrine resistance.

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Section: Discussionmentioning

confidence: 91%

FGF2 induces breast cancer growth through ligand‐independent activation and recruitment of ERα and PRBΔ4 isoform to MYC regulatory sequences

Giulianelli

Riggio

Guillardoy

et al. 2019

Intl Journal of Cancer

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“…E2F and c‐Myc are well‐known transcription factors that are involved in cell cycle progression and cancer malignancy. Small molecules that inhibit E2F or c‐Myc transcriptional activity induce cell cycle arrest at the G0/G1 phase . On the other hand, the inhibition of ZNF143 by YPC‐21661 induced G2/M arrest (Fig.…”

Section: Discussionmentioning

confidence: 97%

YPC‐21661 and YPC‐22026, novel small molecules, inhibit ZNF143 activity in vitro and in vivo

et al. 2017

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Zinc‐finger protein 143 (ZNF143) is a transcription factor that is involved in anticancer drug resistance and cancer cell survival. In the present study, we identified a novel small molecule N‐(5‐bromo‐2‐methoxyphenyl)‐3‐(pyridine‐3‐yl) propiolamide (YPC‐21661) that inhibited ZNF143 promoter activity and down‐regulated the expression of the ZNF143‐regulated genes, RAD51, PLK1, and Survivin, by inhibiting the binding of ZNF143 to DNA. In addition, YPC‐21661 was cytotoxic and induced apoptosis in the human colon cancer cell line, HCT116 and human prostate cancer cell line, PC‐3. 2‐(pyridine‐3‐ylethynyl)‐5‐(2‐(trifluoromethoxy)phenyl)‐1,3,4‐oxadiazole (YPC‐22026), a metabolically stable derivative of YPC‐21661, induced tumor regression accompanied by the suppression of ZNF143‐regulated genes in a mouse xenograft model. The present study revealed that the inhibition of ZNF143 activity by small molecules induced tumor regression in vitro and in vivo; therefore, ZNF143 is a promising target of cancer therapeutics.

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“…10058-F4 interacts with the amino acids 402-409 of the C-terminal bHLH-LZ domain of MYC (34), thereby preventing MYC/MAX dimerization. In vitro, 10058-F4 was shown to impair proliferation and to induce apoptosis of human PDAC cells (35). However, in vivo, no activity of 10058-F4 was detected toward s.c. transplanted human Panc1 cells, but 10058-F4 synergistically induced apoptosis together with gemcitabine (35).…”

Section: Targeting Myc Directlymentioning

confidence: 99%

“…In vitro, 10058-F4 was shown to impair proliferation and to induce apoptosis of human PDAC cells (35). However, in vivo, no activity of 10058-F4 was detected toward s.c. transplanted human Panc1 cells, but 10058-F4 synergistically induced apoptosis together with gemcitabine (35). These data might be explained by the inappropriate pharmacokinetics of 10058-F4 observed in vivo (36).…”

Section: Targeting Myc Directlymentioning

confidence: 99%

Concepts to Target MYC in Pancreatic Cancer

Wirth

Mahboobi

Krämer

et al. 2016

Molecular Cancer Therapeutics

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Current data suggest that MYC is an important signaling hub and driver in pancreatic ductal adenocarcinoma (PDAC), a tumor entity with a strikingly poor prognosis. No targeted therapies with a meaningful clinical impact were successfully developed against PDAC so far. This points to the need to establish novel concepts targeting the relevant drivers of PDAC, like KRAS or MYC. Here, we discuss recent developments of direct or indirect MYC inhibitors and their potential mode of action in PDAC.

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Inhibition of c-Myc by 10058-F4 induces growth arrest and chemosensitivity in pancreatic ductal adenocarcinoma

Cited by 32 publications

References 23 publications

FGF2 induces breast cancer growth through ligand‐independent activation and recruitment of ERα and PRBΔ4 isoform to MYC regulatory sequences

FGF2 induces breast cancer growth through ligand‐independent activation and recruitment of ERα and PRBΔ4 isoform to MYC regulatory sequences

YPC‐21661 and YPC‐22026, novel small molecules, inhibit ZNF143 activity in vitro and in vivo

Concepts to Target MYC in Pancreatic Cancer

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