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

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

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.

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / enzymology
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Movement / drug effects*
  • Cell Survival / drug effects
  • Drug Resistance, Neoplasm*
  • Female
  • Focal Adhesion Kinase 1 / genetics
  • Focal Adhesion Kinase 1 / metabolism*
  • Humans
  • Integrin alpha2 / metabolism
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • Melanoma / drug therapy*
  • Melanoma / enzymology
  • Melanoma / pathology
  • Mice, Nude
  • Multiprotein Complexes / antagonists & inhibitors*
  • Multiprotein Complexes / metabolism
  • Neoplasm Invasiveness
  • Phosphatidylinositol 3-Kinase / metabolism
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology*
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / metabolism
  • RNA Interference
  • Receptor, IGF Type 1
  • Receptors, Somatomedin / antagonists & inhibitors*
  • Receptors, Somatomedin / genetics
  • Receptors, Somatomedin / metabolism
  • Signal Transduction / drug effects
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / enzymology
  • Skin Neoplasms / genetics
  • Skin Neoplasms / pathology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • TOR Serine-Threonine Kinases / metabolism
  • Time Factors
  • Transfection
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • IGF1R protein, human
  • Integrin alpha2
  • Multiprotein Complexes
  • Protein Kinase Inhibitors
  • Receptors, Somatomedin
  • MTOR protein, human
  • Phosphatidylinositol 3-Kinase
  • Receptor, IGF Type 1
  • Focal Adhesion Kinase 1
  • PTK2 protein, human
  • AKT1 protein, human
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • Proto-Oncogene Proteins c-akt
  • TOR Serine-Threonine Kinases