Abstract P1-09-06: Blocking ER coregulator signaling enhances CDK4/6 inhibitor palbociclib therapy in ER-positive advanced breast cancer

Abstract

BACKGROUND: Recently,CDK4/6 inhibitors in combination with endocrine therapy (AE/AI/SERDs) is approved for the treatment of ER+ advanced breastcancer (BCa). However, not all patients benefit from CDK4/6 inhibitors therapy. Emerging studies indicate many therapy-resistant tumors retainER signaling, via interaction with critical oncogenic coregulatorproteins. Considering complex signaling interplay of ER and CDK4/6 axis, combination therapy of CDK inhibitor with other potent ER-targeted agents that block ER coregulatory signaling may extend the efficacy and may prevent the development of resistance to the CDK4/6 inhibitors. We recently developed a small organic molecule, ER coregulator binding modulator ERX-11 (EtiraRx-11). The objective of this study is to test the utility of novel combination therapy of ERX-11 with CDK4/6 inhibitor palbociclib in treating therapy resistant advanced BCa. METHODS: We have utilized multiple therapy sensitive and therapy-resistant BCa models with various genetic backgrounds. We tested efficacy using both acquired resistance and engineered models that express ER mutations or oncogenes. Efficacy of combination therapy was tested using established in vitro assays including, MTT, colony formation, apoptosis, and cell cycle progression. Mechanistic studies were conducted using reporter gene assays, gene expression, RNA-seq analysis and signaling alterations. Patient-derived BCa explant and Xenograft studies were used to determine the in vivo efficacy of the combination therapy. RESULTS: ERX-11 effectively blocked ER-mediated and ER-coregulator mediated oncogenic signaling and has potent anti-proliferative activity against both endocrine therapy-sensitive and therapy-resistant BCa cells. Mechanistic studies using IP-Mass spectrometry showed that ERX-11 blocks the interaction between a subset of coregulators with ER in resistant BCa models. ERX-11 exhibited potent anti-proliferative activity against therapy-sensitive and therapy-resistant ER-driven BCa cells in vitro, in xenograft models in vivo and in patient-derived breast tumor explants ex vivo. Co-treatment of ERX-11 with palbociclib synergistically reduced cell viability and induced apoptosis of therapy sensitive and resistant BCa model cells. Importantly, combination therapy of ERX-11 and the palbociclib synergistically reduced the growth and induced apoptosis of tamoxifen and letrozole resistant xenograft tumors compared to either drug alone. RNA-seq studies revealed that combinational treatment with ERX-11 and palbociclib uniquely activated p53 and unfolded response mediated apoptotic pathways and suppressed E2F and Myc target genes. Biochemical studies confirmed combination therapy significantly altered E2F1 and ER signaling pathways and promoted apoptosis. CONCLUSIONS: Our data support a critical role of blocking ER coregulator signaling in treating therapy resistance in advanced ER+ BCa. Combinational treatment with ERX-11 and palbociclib may overcome/delay endocrine therapy resistance. Citation Format: Viswanadhapalli S, Sareddy GR, Zhou M, Ali E, Li X, Ma S-H, Lee T-K, Tekmal RR, Ahn J-M, Raj GV, Vadlamudi RK. Blocking ER coregulator signaling enhances CDK4/6 inhibitor palbociclib therapy in ER-positive advanced breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-09-06.

Emerging data and future directions for CDK4/6 inhibitor treatment of patients with hormone receptor positive HER2‐non‐amplified metastatic breast cancer

“…Other potent ER‐directed agents in development include the ER coregulatory binding modulator EtiraRx‐11 (ERX‐11), which has demonstrated efficacy in blocking ER and ER‐coregulator mediated oncogenic signaling, and inhibited proliferation of both endocrine‐sensitive and ‐resistant breast cancer cells. Co‐treatment of ERX‐11 with palbociclib showed synergistic activity preclinically in in vitro and in vivo models . Another group of compounds with a unique ER antagonist activity in clinical development are the selective estrogen receptor covalent antagonists (SERCAs), which include H3B‐5942.…”