title: Treatment of Triple-Negative Breast Cancer with TORC1/2 Inhibitors Sustains a Drug-Resistant and Notch-Dependent Cancer Stem Cell Population.
abstract: Approximately 30% of triple-negative breast cancers (TNBC) harbor molecular alterations in PI3K/mTOR signaling, but therapeutic inhibition of this pathway has not been effective. We hypothesized that intrinsic resistance to TORC1/2 inhibition is driven by cancer stem cell (CSC)-like populations that could be targeted to enhance the antitumor action of these drugs. Therefore, we investigated the molecular mechanisms by which PI3K/mTOR inhibitors affect the stem-like properties of TNBC cells. Treatment of established TNBC cell lines with a PI3K/mTOR inhibitor or a TORC1/2 inhibitor increased the expression of CSC markers and mammosphere formation. A CSC-specific PCR array revealed that inhibition of TORC1/2 increased FGF1 and Notch1 expression. Notch1 activity was also induced in TNBC cells treated with TORC1/2 inhibitors and associated with increased mitochondrial metabolism and FGFR1 signaling. Notably, genetic and pharmacologic blockade of Notch1 abrogated the increase in CSC markers, mammosphere formation, and in vivo tumor-initiating capacity induced by TORC1/2 inhibition. These results suggest that targeting the FGFR-mitochondrial metabolism-Notch1 axis prevents resistance to TORC1/2 inhibitors by eradicating drug-resistant CSCs in TNBC, and may thus represent an attractive therapeutic strategy to improve drug responsiveness and efficacy.
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: Neil E
authors.initials: NE
authors.lastname: Bhola
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: Valerie M
authors.initials: VM
authors.lastname: Jansen
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: James P
authors.initials: JP
authors.lastname: Koch
authors.affiliation: Department of Otolaryngology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee.
authors.forename: Luigi
authors.initials: L
authors.lastname: Formisano
authors.affiliation: Cell Imaging Shared Resource, Vanderbilt University, Nashville, Tennessee.
authors.forename: Janice A
authors.initials: JA
authors.lastname: Williams
authors.affiliation: Department of Otolaryngology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Grandis
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tennessee. Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee. Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee. carlos.arteaga@vanderbilt.edu.
authors.forename: Carlos L
authors.initials: CL
authors.lastname: Arteaga
mesh_terms: D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006801:Humans; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes / Q000235:genetics* / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism*; D064726:Triple Negative Breast Neoplasms / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D046912:Multiprotein Complexes; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases