SAN ANTONIO – GS-6510, a novel bromodomain-containing protein 4 (BRD4) inhibitor showed antitumor activity in both endocrine-sensitive and endocrine-resistance breast cancer models, a study presented at the 2016 San Antonio Breast Cancer Symposium (SABCS) has shown.1

Fulvestrant, which is approved for the treatment of hormone receptor (HR)-positive metastatic breast cancer following disease progression with antiestrogen therapy, inhibits ER activity and degrades ER protein in a dose-dependent manner in both preclinical and clinical settings; however, fulvestrant does not completely eliminate ER protein levels, thereby limiting its efficacy. Therefore, additional strategies are needed to more effectively reduce ER levels and reduce their activity.

The bromo and extraterminal domain (BET) protein family includes BRD2, BRD3, BRD4, and BRDT. These proteins are epigenetic readers that bind acetylated lysines on histones and facilitate the recruitment of epigenetic and transcription factors required in gene transcription.

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GS-6510 is a novel BRD4 inhibitor that researchers hypothesized would be active in ER-positive breast cancer. Investigators tested its activity alone and in combination with endocrine therapies in a panel of ER-positive breast cancer parental and endocrine-resistant cell lines, as well as in a patient-derived xenograft model, by assessing cell growth after 6 days of GS-6510 and protein levels after 2 days of GS-6510.

The preclinical study revealed a dose-dependent inhibitory effect of GS-6510 in all of the experimental settings. At a clinically relevant dose, results showed that GS-6510 reduced estrogen-stimulated cell growth and improved the efficacy of endocrine therapies in all parental cell lines.

In the endocrine-sensitive xenograft model, GS-6510 inhibited tumor growth. When administered with fulvestrant, GS-6510 also induced tumor regression and reduced the expression of ER-dependent and cell cycle related genes including CCND1, MYC, and BCL2.

“The epigenetic regulator BRD4 is a suitable target for therapeutic intervention in ER-positive breast cancer,” said Carmine De Angelis, PhD, Osborne-Schiff Lab, Baylor College of Medicine, Houston. “The antitumor efficacy of GS-6510 in endocrine-sensitive and especially in ER-dependent, endocrine-resistant models is worthy of further investigation.”

In endocrine-resistant cell models that continue to rely on, and express, ER, the addition of GS-6510 substantially inhibited cell growth. Researchers observed better suppression of ER levels with GS-6510 plus fulvestrant, but the combination did not result in significantly greater cell growth inhibition compared with the investigational drug alone. Endocrine-resistant models also demonstrated the efficacy of GS-6510 in cell lines exhibiting growth independent of ER.

“The growth inhibitory effects observed in some of the ER-independent endocrine-resistant models suggest that additional genes/pathway involved in endocrine resistance could be affected by GS-6510,” Dr De Angelis added. “Identifying these pathways and determining their predictive role are needed to guide patient selection for future trials.”


1. De Angelis C, Nardone A, Cataldo ML, et al. A novel BRD4 inhibitor enhances endocrine therapy efficacy and circumvents endocrine-resistance in estrogen receptor-positive breast cancer models. Paper presented at: 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX.