title: Rictor/mTORC2 Drives Progression and Therapeutic Resistance of HER2-Amplified Breast Cancers.
abstract: HER2 overexpression drives Akt signaling and cell survival and HER2-enriched breast tumors have a poor outcome when Akt is upregulated. Akt is activated by phosphorylation at T308 via PI3K and S473 via mTORC2. The importance of PI3K-activated Akt signaling is well documented in HER2-amplified breast cancer models, but the significance of mTORC2-activated Akt signaling in this setting remains uncertain. We report here that the mTORC2 obligate cofactor Rictor is enriched in HER2-amplified samples, correlating with increased phosphorylation at S473 on Akt. In invasive breast cancer specimens, Rictor expression was upregulated significantly compared with nonmalignant tissues. In a HER2/Neu mouse model of breast cancer, genetic ablation of Rictor decreased cell survival and phosphorylation at S473 on Akt, delaying tumor latency, penetrance, and burden. In HER2-amplified cells, exposure to an mTORC1/2 dual kinase inhibitor decreased Akt-dependent cell survival, including in cells resistant to lapatinib, where cytotoxicity could be restored. We replicated these findings by silencing Rictor in breast cancer cell lines, but not silencing the mTORC1 cofactor Raptor (RPTOR). Taken together, our findings establish that Rictor/mTORC2 signaling drives Akt-dependent tumor progression in HER2-amplified breast cancers, rationalizing clinical investigation of dual mTORC1/2 kinase inhibitors and developing mTORC2-specific inhibitors for use in this setting. Cancer Res; 76(16); 4752-64. ©2016 AACR.
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Meghan
authors.initials: M
authors.lastname: Morrison Joly
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Donna J
authors.initials: DJ
authors.lastname: Hicks
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Bayley
authors.initials: B
authors.lastname: Jones
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Violeta
authors.initials: V
authors.lastname: Sanchez
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Monica Valeria
authors.initials: MV
authors.lastname: Estrada
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Christian
authors.initials: C
authors.lastname: Young
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Michelle
authors.initials: M
authors.lastname: Williams
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Brent N
authors.initials: BN
authors.lastname: Rexer
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Dos D
authors.initials: dos D
authors.lastname: Sarbassov
authors.affiliation: Department of Biochemistry, McGill University, Quebec, Canada.
authors.forename: William J
authors.initials: WJ
authors.lastname: Muller
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee. The Vanderbilt-Ingram Cancer Center at Vanderbilt University, Vanderbilt University, Nashville, Tennessee.
authors.forename: Dana
authors.initials: D
authors.lastname: Brantley-Sieders
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee. The Vanderbilt-Ingram Cancer Center at Vanderbilt University, Vanderbilt University, Nashville, Tennessee. rebecca.cook@vanderbilt.edu.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Cook
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D002352:Carrier Proteins / Q000378:metabolism*; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D005260:Female; D064593:Heterografts; D006801:Humans; D053208:Kaplan-Meier Estimate; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D046912:Multiprotein Complexes / Q000378:metabolism*; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D046888:Tissue Array Analysis
chemical_list: D002352:Carrier Proteins; D000076225:Mechanistic Target of Rapamycin Complex 2; D046912:Multiprotein Complexes; D000076226:Rapamycin-Insensitive Companion of mTOR Protein; D018719:Erb-b2 Receptor Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases; C492571:RICTOR protein, human; C525637:rictor protein, mouse; C508053:ERBB2 protein, human; C524056:Erbb2 protein, mouse