The combination of NVP-BKM120 with trastuzumab or RAD001 synergistically inhibits the growth of breast cancer stem cells in vivo

Yu,Feng; Zhao,Jing; Hu,Yunhui; Zhou,Yang; Guo,Rong; Bai,Jingchao; Zhang,Sheng; Zhang,Huilai; Zhang,Jin

doi:10.3892/or.2016.4799

The combination of NVP-BKM120 with trastuzumab or RAD001 synergistically inhibits the growth of breast cancer stem cells in vivo

Authors:
- Feng Yu
- Jing Zhao
- Yunhui Hu
- Yang Zhou
- Rong Guo
- Jingchao Bai
- Sheng Zhang
- Huilai Zhang
- Jin Zhang
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Affiliations: The Third Department of Breast Cancer, China Tianjin Breast Cancer Prevention, Treatment and Research Center, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Tianjin 300060, P.R. China, Department of Lymphoma, Tianjin Medical University Cancer Hospital, Sino-US Center for Lymphoma and Leukemia, Tianjin Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, P.R. China
Published online on: May 10, 2016 https://doi.org/10.3892/or.2016.4799
Pages: 356-364

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Abstract

Deregulation of the phosphatidylinositol-3-kinase (PI3K)/Akt signalling pathway is common in breast cancer and is frequently associated with resistance to both traditional chemotherapy and targeted drugs. There is a growing body of evidence indicating that a small subpopulation of self-renewing cells, the so called cancer stem cells (CSC), are responsible for the growth of drug resistant secondary tumors. As many CSCs have upregulated the PI3K/Akt signalling pathway, preclinical and clinical studies are addressing the inhibition of this axis to target drug resistance. We evaluated the susceptibility of breast CSCs to NVP-BKM120 (BKM120), a new generation of PI3K-specific inhibitor, when used individually or in combination with trastuzumab or RAD001 both in vitro and in vivo. For this, a stem-like cell population (SC) was enriched from breast cancer cell lines after mammosphere cultures. We demonstrated that BKM120 inhibits growth, generation of drug-resistant derivatives and SC formation in a panel of four breast cancer cell lines: MCF-7, MDA-MB-231, SK-BR-3 and CAL51. Importantly, BKM120 inhibits the PI3K/Akt signalling pathway in SCs from these cell lines. When BKM120 was used in combination with trastuzumab, a targeted therapy to treat HER2-positive breast cancer, we found synergistic cell growth inhibition, generation of drug resistant cells as well as SC formation from SK-BR-3 cells. Importantly, SK-BR-3 xenograft-derived tumors showed marginal growth when the drug combination was used. We also found a similar synergistic anticancer effect of BKM120 in combination with RAD001, an mTOR inhibitor, when treating triple-negative breast cancer cells in vitro and in both MDA-MB-231 and CAL51- mouse xenografts. Moreover, mouse data indicate that these drug combinations are well tolerated and provide the proof-of-concept and rationale to initiate clinical trials in both HER2-positive and triple-negative breast cancer.

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