Estrogen receptor coregulator binding modulators (ERXs) effectively target estrogen receptor positive human breast cancers

Ganesh V. Raj, Gangadhara Reddy Sareddy, Shihong Ma, Tae Kyung Lee, Suryavathi Viswanadhapalli, Rui Li, Xihui Liu, Shino Murakami, Chien Cheng Chen, Wan Ru Lee, Monica Mann, Samaya Rajeshwari Krishnan, Bikash Manandhar, Vijay K. Gonugunta, Douglas Strand, Rajeshwar Rao Tekmal, Jung Mo Ahn, Ratna K. Vadlamudi

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

The majority of human breast cancer is estrogen receptor alpha (ER) positive. While anti-estrogens/aromatase inhibitors are initially effective, resistance to these drugs commonly develops. Therapy-resistant tumors often retain ER signaling, via interaction with critical oncogenic coregulator proteins. To address these mechanisms of resistance, we have developed a novel ER coregulator binding modulator, ERX-11. ERX-11 interacts directly wiTheR and blocks the interaction between a subset of coregulators with both native and mutant forms of ER. ERX-11 effectively blocks ER-mediated oncogenic signaling and has potent anti-proliferative activity against therapy-sensitive and therapy-resistant human breast cancer cells. ERX-11 is orally bioavailable, with no overt signs of toxicity and potent activity in both murine xenograft and patient-derived breast tumor explant models. This first-in-class agent, with its novel mechanism of action of disrupting critical protein-protein interactions, overcomes the limitations of current therapies and may be clinically translatable for patients with therapy-sensitive and therapy-resistant breast cancers.

Original languageEnglish (US)
Article numbere26857
JournaleLife
Volume6
DOIs
StatePublished - Aug 8 2017

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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    Raj, G. V., Sareddy, G. R., Ma, S., Lee, T. K., Viswanadhapalli, S., Li, R., Liu, X., Murakami, S., Chen, C. C., Lee, W. R., Mann, M., Krishnan, S. R., Manandhar, B., Gonugunta, V. K., Strand, D., Tekmal, R. R., Ahn, J. M., & Vadlamudi, R. K. (2017). Estrogen receptor coregulator binding modulators (ERXs) effectively target estrogen receptor positive human breast cancers. eLife, 6, [e26857]. https://doi.org/10.7554/eLife.26857