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.
Pubmed ID: 28757207 RIS Download
Mesh terms: Animals | Antineoplastic Combined Chemotherapy Protocols | Breast Neoplasms | Cell Line, Tumor | Cell Movement | Cell Survival | Drug Resistance, Neoplasm | Female | Focal Adhesion Kinase 1 | Humans | Integrin alpha2 | Mechanistic Target of Rapamycin Complex 1 | Mechanistic Target of Rapamycin Complex 2 | Melanoma | Mice, Nude | Multiprotein Complexes | Neoplasm Invasiveness | Phosphatidylinositol 3-Kinase | Phosphorylation | Protein Kinase Inhibitors | Proto-Oncogene Proteins c-akt | RNA Interference | Receptors, Somatomedin | Signal Transduction | Skin Neoplasms | TOR Serine-Threonine Kinases | Time Factors | Transfection | Tumor Burden | Xenograft Model Antitumor Assays
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