title: Active kinase profiling, genetic and pharmacological data define mTOR as an important common target in triple-negative breast cancer.
abstract: Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer. Despite response to chemotherapy, relapses are frequent and resistance to available treatments is often seen in the metastatic setting. Therefore, identification of new therapeutic targets is required. With this aim, we have profiled the activation status of 44 receptor tyrosine kinases (RTKs) and their major signaling pathways in patient-derived TNBC tumors. Frequent co-activation of several RTKs as well as the extracellular signal-regulated protein kinases 1 and 2 (Erk1/2) and mammalian target of rapamycin (mTOR) routes was found. Pharmacologic targeting of the activated kinases indicated that agents that attack the mTOR route are more potent and efficient antitumoral treatments than agents targeting RTKs. mTOR signals through two multiprotein complexes, mTORC1 and mTORC2. We used a genetic approach to explore the contribution of each of the two mTOR branches to the regulation of cell number of TNBC cells. RNA interference experiments indicated that mTORC1 predominated over mTORC2 in the control of TNBC cell proliferation. Moreover, RNA interference of mTOR had a superior antiproliferative action than separately acting on mTORC1 or mTORC2. To analyze the relevance of mTOR targeting in vivo, we used mice with TNBC. Treatment of these mice with BEZ235, a drug that targets mTOR, slowed tumor growth. Mechanistically, BEZ235 delayed cell cycle progression without affecting cell viability. Our results show that TNBCs are particularly sensitive to inhibition of the mTOR pathway, and indicate that mTOR targeting may be a more efficient anti-TNBC therapy than exclusively acting on the mTORC1 branch of the pathway. This is relevant as most mTOR inhibitors used in the clinic act on mTORC1. Collectively with the fact that BEZ235 synergized with drugs commonly used in the treatment of TNBC, our data support the clinical development of agents that act on mTOR as a therapy for this disease.
authors.affiliation: Instituto de Biología Molecular y Celular del Cáncer, CSIC-Universidad de Salamanca, Salamanca, Spain.
authors.forename: J C
authors.initials: JC
authors.lastname: Montero
authors.affiliation: Instituto de Biología Molecular y Celular del Cáncer, CSIC-Universidad de Salamanca, Salamanca, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Esparís-Ogando
authors.affiliation: Instituto de Biología Molecular y Celular del Cáncer, CSIC-Universidad de Salamanca, Salamanca, Spain.
authors.forename: M F
authors.initials: MF
authors.lastname: Re-Louhau
authors.affiliation: Instituto de Biología Molecular y Celular del Cáncer, CSIC-Universidad de Salamanca, Salamanca, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Seoane
authors.affiliation: Pathology Department, Hospital Clínico Universitario de Salamanca, Salamanca, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Abad
authors.affiliation: Servicio de Oncología Médica, Complejo Hospitalario Universitario de Albacete, and AECC Unit, Albacete, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Calero
authors.affiliation: 1] Servicio de Oncología Médica, Complejo Hospitalario Universitario de Albacete, and AECC Unit, Albacete, Spain [2] Division of Medical Oncology and Hematology, Princess Margaret Hospital, University of Toronto, Toronto, Ontario, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Ocaña
authors.affiliation: Instituto de Biología Molecular y Celular del Cáncer, CSIC-Universidad de Salamanca, Salamanca, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Pandiella
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008807:Mice, Inbred BALB C; D046912:Multiprotein Complexes / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011804:Quinolines / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics
chemical_list: D007093:Imidazoles; D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; D011804:Quinolines; D020794:Receptor Protein-Tyrosine Kinases; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; C531198:dactolisib