Figure 3.

Proposed model of how dietary factors could modulate resistance to mTOR inhibitors. (A) One of the most pervasive mechanisms of resistance to rapalogs is the hyperactivation of mTORC2 signaling and downstream AKT, PKC and SGK signaling following mTORC1-S6K inhibition. Furthermore, in the context of hyperglycemia and hyperinsulinemia observed in patients with type-2 diabetes and even following chronic rapalog treatment, feedback activation of the insulin receptor may occur which overrides the therapeutic benefit of these inhibitors. In this scenario, a very low carbohydrate diet such as the ketogenic diet could lower the metabolic feedback signals that hyperactivate resistance pathways downstream of the insulin receptor. (B) Schematic of how altering dietary fat content in the form of pro-inflammatory ω-6 or anti-inflammatory ω-3 FA ratios could impact the physiology of adipose tissue that shapes autocrine/paracrine signaling networks in the tumor microenvironment. In this context, “Western” diets containing an excess of ω-6 FAs such as linoleic and arachidonic acid may cooperate with the feedback hyperactivation of AKT and MAPK/ERK signaling observed following first- and second-generation mTOR inhibitor treatment to drive therapy resistance. Conversely, a diet rich in ω-3 FAs such as linolenic acid, EPA, and DHA may suppress the reactivation of these oncogenic pathways. Dotted lines or outlines surrounding enzymes denote downregulation/inhibition. Abbreviations: T2D, type 2 diabetes; INSR, insulin receptor; Grb10, growth factor receptor bound protein 10; PIP₂, phosphatidylinositol (4,5)-bisphosphate; PIP₃, phosphatidylinositol (3,4,5)-trisphosphate; PDK1, phosphoinositide-dependent kinase 1; SGK1, serum and glucocorticoid-induced protein kinase 1; PKC, protein kinase C; AA, arachidonic acid; PGE2, prostaglandin E2; ALA, alpha-linolenic acid; EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; PGE3, prostaglandin E3; EP1-4, Prostaglandin E2 receptor 1-4; HER2, receptor tyrosine-protein kinase erbB-2.