The novel combination of estrogen receptor (ER) coregulator binding modulator (ERX-11) and palbociclib may delay, or even overcome, endocrine therapy resistance in women with ER-positive advanced breast cancer, according to a group of researchers from the University of Texas (UT) Healthcare System. They reported their findings during the San Antonio Breast Cancer Symposium on Wednesday, December 6.
Although significant advancements have been made in identifying patients with breast cancer who benefit from CDK4/6 inhibitors, still not all patients do. Recent data have suggested that therapy-resistant tumors retain ER signaling through their interaction with oncogenic coregulator proteins. UT researchers recently developed a small organic molecule, ER-coregulator binding modulator ERX-11, dubbed EtiraRx-11. The hypothesis was that the combination therapy of a CDK inhibitor with other ER-targeted agents that block ER-coregulator signaling may extend efficacy and prevent the development of CDK4/6 inhibitor resistance.
The group found that ERX-11 effectively blocked ER-mediated and ER-coregulator mediated oncogenic signaling and had antiproliferative activity against both endocrine therapy-sensitive and therapy-resistant breast cancer cells. Additionally, through mechanistic studies using IP-mass spectrometry, the group showed that ERX-11 blocks the interaction between a subset of coregulators with ER in resistant breast cancer models. ERX-11 also illustrated potent antiproliferative activity against therapy-sensitive and therapy-resistant ER-driven breast cancer cells in vitro, in xenograft models in vivo, and in patient-derived breast tumor explants ex vivo. Cotreatment of ERX-11 with palbociclib “synergistically reduced cell viability and induced apoptosis of therapy-sensitive and -resistant breast cancer model cells.” The group said that the combination ERX-11/palbociclib therapy reduced the growth and induced apoptosis of tamoxifen- and letrozole-resistant xenograft tumors compared with either drug alone. Combination treatment also uniquely activated p53, unfolded response mediated apoptic pathways, and suppressed E2F and Myc target genes. Finally, biochemical studies confirmed the combination therapy significantly altered the E2F1 and ER signaling pathways and promoted apoptosis.