Abstract 4148: Novel ERX-11 and CDK4/6 inhibitor combination therapy for treating therapy resistant breast cancer

Abstract

Abstract BACKGROUND: The majority of the breast cancer is estrogen receptor alpha (ESR1) positive. While tamoxifen and letrozole therapies are effective, therapy resistance is common. Importantly, both therapy-sensitive and therapy-resistant tumors retain ESR1 signaling, via interaction with critical oncogenic coregulator proteins. Further, resistant tumors commonly acquire cyclin D1:CDK4/6 signaling via multiple mechanisms, cyclin D1 can independently activate ESR1 and thus contribute to estrogen independence of ESR+ tumor. Currently, CDK4/6 inhibitors in clinical trials for treating breast cancer, however, considering complex signaling interplay of estrogen and CDK axis, combination therapy of CDK inhibitor with other potent ESR1 targeted agents may have better utility and may prevent development of resistance to the CDK4/6 inhibitors. We recently developed a small organic molecule, ESR1 coregulator binding inhibitor 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 cancer. METHODS: We have utilized multiple therapy sensitive and therapy-resistant models with various genetic back grounds. We tested efficacy using both acquired resistance and engineered models that express ESR1 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 and signaling alterations. Xenograft studies were used to determine the in vivo efficacy of the combination therapy. RESULTS: ERX-11 effectively blocked ESR1-mediated oncogenic signaling and has potent anti-proliferative activity against therapy-sensitive and therapy-resistant breast cancer cells. Mechansistic studies showed that ERX-11 blocks the interaction between a subset of coregulators with both native and mutant forms of ESR1. ERX-11 showed potent activity in both preclinical xenograft models and patient-derived breast tumor explant models. Co-treatment of ERX-11 with palbociclib synergistically reduced cell viability and induced apoptosis of therapy sensitive and resistant breast cancer 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. Mechanistic studies showed combination therapy significantly altered E2F1 and ESR1 signaling pathways and promoted apoptosis. CONCLUSIONS: Collectively our studies have discovered a novel combinational treatment with ERX-11 and palbociclib for patients with therapy-sensitive and therapy-resistant breast cancers. Citation Format: Suryavathi Viswanadhapalli, Gangadhara Reddy Sareddy, Shi-Hong Ma, Tae-Kyung Lee, Rajeshwar Rao Tekmal, Jung-Mo Ahn, Ganesh Raj, Ratna K. Vadlamudi. Novel ERX-11 and CDK4/6 inhibitor combination therapy for treating therapy resistant breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4148. doi:10.1158/1538-7445.AM2017-4148