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Mol Cell. 2017 Aug 3;67(3):512-527.e4. doi: 10.1016/j.molcel.2017.06.033. Epub 2017 Jul 27.

Focal Adhesion- and IGF1R-Dependent Survival and Migratory Pathways Mediate Tumor Resistance to mTORC1/2 Inhibition.

Author information

1
Department of Pharmacology, Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: syoon1@uic.edu.
2
Department of Pharmacology, Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065, USA.
3
Department of Medicine, Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065, USA.
4
Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
5
Department of Cancer Biology, University of Cincinnati, Cincinnati, OH 45267, USA.
6
Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada.
7
Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montreal, QC H3T 1J4, Canada.
8
Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA.
9
Department of Pharmacology, Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065, USA. Electronic address: jblenis@med.cornell.edu.

Abstract

Aberrant signaling by the mammalian target of rapamycin (mTOR) contributes to the devastating features of cancer cells. Thus, mTOR is a critical therapeutic target and catalytic inhibitors are being investigated as anti-cancer drugs. Although mTOR inhibitors initially block cell proliferation, cell viability and migration in some cancer cells are quickly restored. Despite sustained inhibition of mTORC1/2 signaling, Akt, a kinase regulating cell survival and migration, regains phosphorylation at its regulatory sites. Mechanistically, mTORC1/2 inhibition promotes reorganization of integrin/focal adhesion kinase-mediated adhesomes, induction of IGFR/IR-dependent PI3K activation, and Akt phosphorylation via an integrin/FAK/IGFR-dependent process. This resistance mechanism contributes to xenograft tumor cell growth, which is prevented with mTOR plus IGFR inhibitors, supporting this combination as a therapeutic approach for cancers.

KEYWORDS:

Akt; dual mTORC1/2 inhibition; mTORC1; mTORC2; tumor resistance

PMID:
28757207
PMCID:
PMC5698809
DOI:
10.1016/j.molcel.2017.06.033
[Indexed for MEDLINE]
Free PMC Article

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