title: The combination of NVP-BKM120 with trastuzumab or RAD001 synergistically inhibits the growth of breast cancer stem cells in vivo.
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.
authors.affiliation: 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.
authors.forename: Feng
authors.initials: F
authors.lastname: Yu
authors.affiliation: 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.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: 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.
authors.forename: Yunhui
authors.initials: Y
authors.lastname: Hu
authors.affiliation: 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.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: 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.
authors.forename: Rong
authors.initials: R
authors.lastname: Guo
authors.affiliation: 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.
authors.forename: Jingchao
authors.initials: J
authors.lastname: Bai
authors.affiliation: 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.
authors.forename: Sheng
authors.initials: S
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Huilai
authors.initials: H
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000631:Aminopyridines / Q000008:administration & dosage; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004357:Drug Synergism; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D009025:Morpholines / Q000008:administration & dosage; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000068878:Trastuzumab / Q000008:administration & dosage; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000631:Aminopyridines; D009025:Morpholines; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C571178:NVP-BKM120; C508053:ERBB2 protein, human