mTORC2 activity in brain cancer: Extracellular nutrients are required to maintain oncogenic signaling

Abstract

Mutations in growth factor receptor signaling pathways are common in cancer cells, including the highly lethal brain tumor glioblastoma (GBM) where they drive tumor growth through mechanisms including altering the uptake and utilization of nutrients. However, the impact of changes in micro-environmental nutrient levels on oncogenic signaling, tumor growth, and drug resistance is not well understood. We recently tested the hypothesis that external nutrients promote GBM growth and treatment resistance by maintaining the activity of mechanistic target of rapamycin complex 2 (mTORC2), a critical intermediate of growth factor receptor signaling, suggesting that altered cellular metabolism is not only a consequence of oncogenic signaling, but also potentially an important determinant of its activity. Here, we describe the studies that corroborate the hypothesis and propose others that derive from them. Notably, this line of reasoning raises the possibility that systemic metabolism may contribute to responsiveness to targeted cancer therapies.

Keywords: genetic-environment interaction; genetics; glioblastoma; mTOR; metabolic reprogramming.

Figure 1

mTORC2 signaling is elevated in many cancers via two distinct mechanisms. In non-small cell lung cancer and melanoma, Rictor amplification drives mTORC2 signaling while mTORC2 signaling is hyper-activated by upstream growth factor signaling pathway mutations in prostate cancer, leukemia and GBM. Hyper-activated mTORC2 can drive tumor formation, remodel an epigenome and transcription factor network, and facilitate metabolic reprogramming through an oncogenic transcription factor c-Myc. del, deletion; EGFRvIII, epidermal growth factor receptor variant III; GBM, glioblastoma multiforme; mut, mutation; NSCLC, non-small cell lung cancer; PI3K, phosphoinositide 3-kinase; PIK3CA, phosphatidylinositol (4,5)-bisphosphate 3-kinase catalytic subunit alpha; PIP2, phosphatidylinositol (4,5)-bisphosphate; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; PTEN, phosphatase and tensin homolog deleted on chromosome 10; TF, transcriptional factor.

Figure 2

Extracellular nutrients are required to maintain growth factor receptor signaling through mTORC2. mTORC2 forms an auto-activation loop (i) by promoting glucose/acetate uptake and acetyl-CoA production through its downstream pathways of c-Myc [11] and (ii) by an activation of mTORC2 through acetyl-CoA-dependent acetylation of Rictor [36]. By these mechanisms, GBM cells with activated mTORC2 are resistant to molecularly targeted therapies toward their upstream stimulators, including EGFR. This study suggests that altered cellular metabolism is not only a consequence of oncogenic signaling, but also an important determinant of its activity, raising the possibility that systemic metabolism may contribute to resistance to targeted cancer therapies [59]. Ac, acetyl-group; Ac-CoA, acetyl-CoA.