Reference Detail

Ref Type

Journal Article

PMID

(25612620)

Authors

Wang S, Chen XA, Hu J, Jiang JK, Li Y, Chan-Salis KY, Gu Y, Chen G, Thomas C, Pugh BF, Wang Y

Title

ATF4 Gene Network Mediates Cellular Response to the Anticancer PAD Inhibitor YW3-56 in Triple-Negative Breast Cancer Cells.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	14	4	2015 Apr	877-88	Mol Cancer Ther

URL

Abstract Text

We previously reported that a pan-PAD inhibitor, YW3-56, activates p53 target genes to inhibit cancer growth. However, the p53-independent anticancer activity and molecular mechanisms of YW3-56 remain largely elusive. Here, gene expression analyses found that ATF4 target genes involved in endoplasmic reticulum (ER) stress response were activated by YW3-56. Depletion of ATF4 greatly attenuated YW3-56-mediated activation of the mTORC1 regulatory genes SESN2 and DDIT4. Using the ChIP-exo method, high-resolution genomic binding sites of ATF4 and CEBPB responsive to YW3-56 treatment were generated. In human breast cancer cells, YW3-56-mediated cell death features mitochondria depletion and autophagy perturbation. Moreover, YW3-56 treatment effectively inhibits the growth of triple-negative breast cancer xenograft tumors in nude mice. Taken together, we unveiled the anticancer mechanisms and therapeutic potentials of the pan-PAD inhibitor YW3-56.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
YW3-56	YW3-56	1	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
YW3-56				YW3-56 is a peptidylarginine deiminase (PAD) inhibitor with activity against PAD2 and PAD4, which results in decreased histone citrullination and activation of the endoplasmic reticulum stress response, potentially resulting in decreased tumor cell growth (PMID: 22605338, PMID: 25612620).

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
TP53 R280K	triple-receptor negative breast cancer	sensitive	YW3-56	Preclinical - Cell line xenograft	Actionable	In a preclinical study, YW3-56 inhibited proliferation of a human triple-negative breast cancer (TNBC) cell line harboring TP53 R280K in culture and inhibited tumor growth in TP53 R280K-mutant TNBC cell line xenograft models (PMID: 25612620).	25612620