Dual Src Kinase/Pretubulin Inhibitor KX-01, Sensitizes ERalpha-negative Breast Cancers to Tamoxifen through ERalpha Reexpression.

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Anbalagan M, Sheng M, Fleischer B, Zhang Y, Gao Y, Hoang V, Matossian M, Burks HE, Burow ME, Collins-Burow BM, Hangauer D, Rowan BG

Dual Src Kinase/Pretubulin Inhibitor KX-01, Sensitizes ERalpha-negative Breast Cancers to Tamoxifen through ERalpha Reexpression.

Mol Cancer Res. 2017 Nov;15(11):1491-1502. doi: 10.1158/1541-7786.MCR-16-0297-T. Epub 2017 Jul 27.

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28751463 [ View in PubMed
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Abstract

Unlike breast cancer that is positive for estrogen receptor-alpha (ERalpha), there are no targeted therapies for triple-negative breast cancer (TNBC). ERalpha is silenced in TNBC through epigenetic changes including DNA methylation and histone acetylation. Restoring ERalpha expression in TNBC may sensitize patients to endocrine therapy. Expression of c-Src and ERalpha are inversely correlated in breast cancer suggesting that c-Src inhibition may lead to reexpression of ERalpha in TNBC. KX-01 is a peptide substrate-targeted Src/pretubulin inhibitor in clinical trials for solid tumors. KX-01 (1 mg/kg body weight-twice daily) inhibited growth of tamoxifen-resistant MDA-MB-231 and MDA-MB-157 TNBC xenografts in nude mice that was correlated with Src kinase inhibition. KX-01 also increased ERalpha mRNA and protein, as well as increased the ERalpha targets progesterone receptor (PR), pS2 (TFF1), cyclin D1 (CCND1), and c-myc (MYC) in MDA-MB-231 and MDA-MB-468, but not MDA-MB-157 xenografts. MDA-MB-231 and MDA-MB-468 tumors exhibited reduction in mesenchymal markers (vimentin, beta-catenin) and increase in epithelial marker (E-cadherin) suggesting mesenchymal-to-epithelial transition (MET). KX-01 sensitized MDA-MB-231 and MDA-MB-468 tumors to tamoxifen growth inhibition and tamoxifen repression of the ERalpha targets pS2, cyclin D1, and c-myc. Chromatin immunoprecipitation (ChIP) of the ERalpha promoter in KX-01-treated tumors demonstrated enrichment of active transcription marks (acetyl-H3, acetyl-H3Lys9), dissociation of HDAC1, and recruitment of RNA polymerase II. Methylation-specific PCR and bisulfite sequencing demonstrated no alteration in ERalpha promoter methylation by KX-01. These data demonstrate that in addition to Src kinase inhibition, peptidomimetic KX-01 restores ERalpha expression in TNBC through changes in histone acetylation that sensitize tumors to tamoxifen.Implications: Src kinase/pretubulin inhibitor KX-01 restores functional ERalpha expression in ERalpha(-) breast tumors, a novel treatment strategy to treat triple-negative breast cancer. Mol Cancer Res; 15(11); 1491-502. (c)2017 AACR.

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