The novel bromodomain-containing protein 4 (BRD4) inhibitor GS-6510 demonstrated anti-tumor activity in endocrine-sensitive and endocrine-resistant breast cancer models, according to a study that will be presented at the 2016 San Antonio Breast Cancer Symposium (SABCS).1

The selective estrogen receptor (ER) down-regulator (SERD) fulvestrant inhibits ER activity and degrades ER protein in a dose-dependent manner in both preclinical and clinical settings, though fulvestrant does not completely eliminate ER protein levels, which limits its efficacy. Additional strategies are needed to more completely reduce ER levels and activity.

To evaluate the efficacy of GS-6510, researchers 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. Investigators assessed cell growth after 6 days of GS-6510 and protein levels after 2 days of GS-6510.

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Results showed a dose-dependent inhibitory effect of GS-6510 in all of the experimental settings. At a clinically relevant dose, researchers found that GS-6510 reduced estrogen-stimulated cell growth and enhanced the efficacy of endocrine therapies in all parental cell lines.

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

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 lead to significantly greater cell growth inhibition compared with GS-6510 alone. Endocrine-resistant models also demonstrated the efficacy of GS-6510 in cell lines exhibiting growth independent of ER.

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The findings suggest that GS-6510 is worthy of further clinical investigation. The identification of these pathways may help guide patient selection for future studies of this novel BRD4 inhibitor alone and in combination with endocrine therapy.


  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 (SABCS); December 6-10, 2016; San Antonio, TX.