Abstract 3078: GSK-3 inhibitor 9ING41 potentiates the antitumor effects of CPT-11 in human breast cancer

Abstract

Abstract Glycogen Synthase Kinase-3beta (GSK-3beta), a serine/threonine protein kinase, has been demonstrated to be potential therapeutic target in human breast cancer. Our objective was to evaluate novel GSK-3 inhibitors alone and in combination with chemotherapeutic drugs for the targeted therapy of breast cancer. Using a short-term treatment, we found that the GSK-3 inhibitor 9ING41 significantly potentiates the antitumor effects of CPT-11, cisplatin and 5-FU to inhibit breast cancer cell growth. We established hormone-refractory BC-1 and BC-2 patient-derived xenograft (PDX) tumor models from metastatic pleural effusions that were obtained from breast cancer patients. We considered BC-1 and BC-2 PDX tumors as chemoresistant, because metastatic disease progressed in both cases in despite of the fact that patients received many cycles of chemotherapy. Although we found that BC-1 and BC-2 PDX tumors express estrogen receptor (ER), both PDX tumors carried activating mutations in ESR1. These mutations confer ligand-independent activity of the ER in tamoxifen-resistant breast tumors. We found that BC-1 and BC-2 PDX tumors grew without estradiol supplementation in immunodeficient mice, which suggests a hormone-refractory nature of these tumors. We found that GSK-3 inhibitor 9ING41 potentiates the effects of chemotherapeutic drug CPT-11, and leads to the regression of BC-1 and BC-2 breast PDX tumors. Our results demonstrate inhibition of GSK-3 as a promising therapeutic approach to overcome breast cancer chemoresistance, and identify GSK-3 inhibitor 9ING41 as a drug candidate for the targeted therapy of human breast cancer. Citation Format: Andrey Ugolkov, Irina Gaisina, Kevin White, Alan Kozikowski, Thomas O’Halloran, Andrew Mazar. GSK-3 inhibitor 9ING41 potentiates the antitumor effects of CPT-11 in human breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3078.