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|Ref Type||Journal Article|
|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||Molecular cancer therapeutics|
|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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|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|