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

• Published in: eLife 2017-08, Vol.6
• Main Authors: Raj, Ganesh V, Sareddy, Gangadhara Reddy, Ma, Shihong, Lee, Tae-Kyung, Viswanadhapalli, Suryavathi, Li, Rui, Liu, Xihui, Murakami, Shino, Chen, Chien-Cheng, Lee, Wan-Ru, Mann, Monica, Krishnan, Samaya Rajeshwari, Manandhar, Bikash, Gonugunta, Vijay K, Strand, Douglas, Tekmal, Rajeshwar Rao, Ahn, Jung-Mo, Vadlamudi, Ratna K
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animal models; Animals; Aromatase; Breast cancer; Breast Neoplasms - drug therapy; Cancer Biology; Care and treatment; Cell Line, Tumor; coagulator binding modulator; Competition; coregulators; Disease Models, Animal; Drug resistance; Endocrine therapy; estrogen receptor; Estrogen Receptor Antagonists - administration & dosage; Estrogen Receptor Antagonists - metabolism; Estrogen receptors; Genetic aspects; Gynecology; Health aspects; Heterografts; Humans; Laboratories; Ligands; Metastasis; Mice; Neoplasm Transplantation; Obstetrics; Organ Culture Techniques; Protein Binding; Protein interaction; Receptors, Estrogen - metabolism; Signal Transduction - drug effects; Software; Toxicity; Tumors; Xenografts
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/elife.26857

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 with ER 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.