Abstract 650: Reparixin, CXCR1/2 inhibitor in combination with CDK4/6 inhibitors attenuates endocrine resistant breast cancer growth and metastasis

Abstract

Abstract Various endocrine therapies have been developed such as selective estrogen receptor modulation (SERM), selective estrogen receptor downregulator (SERD) and ligand deprivation using aromatase inhibitors (AI). Tamoxifen (TAM), a SERM and AIs are the most commonly used adjuvant treatment for postmenopausal women with early-stage estrogen receptor positive breast cancer. Despite the relative safety and significant anti-neoplastic and chemopreventive activities of tamoxifen and AIs, many initially responsive breast tumors develop resistance and ultimately recur. Many underlying molecular events that confer resistance are known, but a unifying theme is yet to be revealed. While the tumor microenvironment is being increasingly recognized as a key factor in multiple stages of disease progression, particularly local resistance, immune-escaping, and distant metastasis, our previous work shows that the critical molecular and cellular players secreted from a crosstalk between breast cancer cells and stromal cells can regulate the tumor growth and process of metastasis in breast cancer. In this report, using established endocrine resistant breast cancer (ERBC) cells and ESR1 mutant cells (Y537S and D538G), we screened the secreted factors in crosstalk between cancer cells and fibroblasts using cytokine antibody arrays and found that CXCL1 is highly upregulated in fibroblasts. To investigate a potential impact given the current clinical landscape of endocrine resistant breast cancer, we performed a high throughput cell-based screen to identify effective combinations of drugs that will be tested in vivo using reparixin, CXCR1/2 inhibitor, tamoxifen (SERM), fulvestrant (SERD), and CDK4/6 inhibitors (Palbociclib and Ribociclib) in co-culture with ERBC cells and fibroblast. Significantly, reparixin decreased ERBC cell viability compared to vehicle while reparixin in combination with tamoxifen and fulvestrant, enhanced the inhibitor effects in ERBC cell growth. We found that the combination treatment of reparixin and Palbociclib and ribociclib significantly inhibited ERBC cell growth and migration compared the single treatment. The inhibitory effect of reparixin was higher in combination with CDK4/6 inhibitors that the combination with tamoxifen and fulvestrant. Furthermore, reparixin in combination with CDK4/6 inhibitors decreased ERBC cell migration and promotes apoptosis.These findings implicate CXCL1 signaling as a critical event in ERBC tumor growth and metastasis via crosstalk between cancer cells and stromal components. Further, these studies suggest that CXCL1 act as key regulators orchestrating ERBC. Therefore, we have provided evidence that supports the hypothesis that functional inhibition of the CXCL1 and CDK4/6 signaling pathway has the potential to circumvent ERBC growth and metastasis. Citation Format: Sneha Pandithar, Olivia Reff, Kideok Jin. Reparixin, CXCR1/2 inhibitor in combination with CDK4/6 inhibitors attenuates endocrine resistant breast cancer growth and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 650.