Active kinase profiling, genetic and pharmacological data define mTOR as an important common target in triple-negative breast cancer

Oncogene. 2014 Jan 9;33(2):148-56. doi: 10.1038/onc.2012.572. Epub 2012 Dec 17.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle Checkpoints
  • Enzyme Activation
  • Female
  • Humans
  • Imidazoles / therapeutic use
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • Mice
  • Mice, Inbred BALB C
  • Multiprotein Complexes / physiology
  • Protein Kinase Inhibitors / therapeutic use*
  • Quinolines / therapeutic use
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • TOR Serine-Threonine Kinases / physiology
  • Triple Negative Breast Neoplasms / drug therapy*
  • Triple Negative Breast Neoplasms / enzymology
  • Triple Negative Breast Neoplasms / genetics

Substances

  • Imidazoles
  • Multiprotein Complexes
  • Protein Kinase Inhibitors
  • Quinolines
  • TOR Serine-Threonine Kinases
  • Receptor Protein-Tyrosine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • dactolisib