Oncogenic EGFR Signaling Activates an mTORC2–NF-κB Pathway That Promotes Chemotherapy Resistance

Abstract

Although it is known that mTOR complex 2 (mTORC2) functions upstream of Akt, the role of this protein kinase complex in cancer is not well understood. Through an integrated analysis of cell lines, in vivo models and clinical samples, we demonstrate that mTORC2 is frequently activated in glioblastoma (GBM), the most common malignant primary brain tumor of adults. We show that the common activating epidermal growth factor receptor (EGFR) mutation (EGFRvIII) stimulates mTORC2 kinase activity, which is partially suppressed by PTEN. mTORC2 signaling promotes GBM growth and survival, and activates NF-κB. Importantly, this mTORC2-NF-κB pathway renders GBM cells and tumors resistant to chemotherapy in a manner independent of Akt. These results highlight the critical role of mTORC2 in GBM pathogenesis, including through activation of NF-κB downstream of mutant EGFR, leading to a previously unrecognized function in cancer chemotherapy resistance. These findings suggest that therapeutic strategies targeting mTORC2, alone or in combination with chemotherapy, will be effective in cancer.

TSC1 controls IL-1β expression in macrophages via mTORC1-dependent C/EBPβ pathway

“…But our data is generally in agreement with previous studies in macrophage cells 19 . Our results are different from those observed in TSC2-deficient MEFs or tumor cells lines and such differences could be attributed to the different cells examined 53 .…”

“…Ghosh et al reported that NF-kB signaling is attenuated in TSC2-deficient MEFs and several human tumor cell lines stimulated by DNA damage 52 . It was also reported that inhibition of mTORC2 signaling abrogates NF-kB activity and also decreases the NF-kB DNA-binding activity in U87/ EGFRvIII cells 53 . In our experiments, we have not observed obvious defect of IKKa/b and IkBa as well as NF-kB p65 nuclear translocation in TSC1-deficient macrophages compared with scramble cells (Figure 4C, F, and G).…”

CC-223, a Potent and Selective Inhibitor of mTOR Kinase: In Vitro and In Vivo Characterization

“…The correlation of sensitivity to CC-223 and IRF4 level suggests a hypothesis that activation of the NFkB pathway may render cells less sensitive to CC-223. Cross-talk between the PI3K and the NFkB pathways have been reported previously (21). However, more studies are needed to confirm this hypothesis.…”

EGFR and NF-κB: partners in cancer

“…EGFRvIII triggers mTORC2 activation, a complex composed of the kinase mTOR bound to unique regulatory proteins, including Rictor and SIN1 [54]. mTORC2 signals to NF-kB through an AKT-independent pathway to promote proliferation, survival, and cisplatin resistance in glioblastomas [55] (Figure 4). Although it is currently unclear whether this pathway is specifically induced in glioma cells resistant to EGFR inhibitors, this study nevertheless shows that NF-kB also acts as a central player in chemotherapy resistance in glioblastoma cells harboring constitutivelyactive EGFR.…”