Abstract
The mammalian target of rapamycin (mTOR) critically regulates several essential biological functions, such as cell growth, metabolism, survival, and immune response by forming two important complexes, namely, mTOR complex 1 (mTORC1) and complex 2 (mTORC2). mTOR signaling is often dysregulated in cancers and has been considered an attractive cancer therapeutic target. Great efforts have been made to develop efficacious mTOR inhibitors, particularly mTOR kinase inhibitors, which suppress mTORC1 and mTORC2; however, major success has not been achieved. With the strong scientific rationale, the intriguing question is why cancers are insensitive or not responsive to mTOR-targeted cancer therapy in clinics. Beyond early findings on induced activation of PI3K/Akt, MEK/ERK, and Mnk/eIF4E survival signaling pathways that compromise the efficacy of rapalog-based cancer therapy, recent findings on the essential role of GSK3 in mediating cancer cell response to mTOR inhibitors and mTORC1 inhibition-induced upregulation of PD-L1 in cancer cells may provide some explanations. These new findings may also offer us the opportunity to rationally utilize mTOR inhibitors in cancer therapy. Further elucidation of the biology of complicated mTOR networks may bring us the hope to develop effective therapeutic strategies with mTOR inhibitors against cancer.
Highlights
The mammalian target of rapamycin and its mediated signaling pathways are critical for maintaining cell homeostasis through regulation of various biological functions, such as cell growth, metabolism, survival, and immune response
Great efforts have been made to develop second-generation ATPcompetitive mammalian target of rapamycin (mTOR) kinase inhibitors (TORKinibs), such as INK128, Torin 1, and AZD8055, which suppress mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) activity, as potential cancer therapeutic agents [11,12], and third-generation bivalent mTOR inhibitors that target mTOR resistance mutations [13] in hopes of developing more efficacious mTOR inhibitors based on the rationale that inhibition of mTORC1 and mTORC2 may achieve better therapeutic efficacy
In an effort to find out the real underlying mechanisms, we have revealed that mTORC2 positively regulates the stabilization of several oncogenic proteins, including cyclin D1, Mcl-1, c-Myc, sterol regulatory element binding protein 1 (SREBP1), and Snail, through inhibiting glycogen synthase kinase-3 (GSK3)-dependent and Skp, Cullin, and F-box containing complex (SCF) E3 ubiquitin E3 ligase-mediated proteasomal degradation [35,36,39, 40]
Summary
Allosteric inhibitors of mTOR and represent first-generation mTOR inhibitors. Some rapalogs (e.g., everolimus/ RAD001 and temsirolimus/CCI-779) are approved by the Food and Drug Administration (FDA) for treatment of certain cancers such as metastatic renal cell carcinoma, pancreatic neuroendocrine tumors, and postmenopausal hormone receptor-positive advanced breast cancer, but the single-agent activity of rapalogs in many other tumor types has been limited [10]. Other mechanisms involving microRNA, long noncoding RNAs, and specific oncogenic signaling pathway activation, can inactivate FBXW7 function in cancer cells [58,59] We assume that these tumors with inactivated SCF E3 ubiquitin ligases, at least some if not all, may not be sensitive to mTOR-targeted cancer therapy. Our recent study failed to reproduce this finding; rather we generated opposite results, that is, inhibition of PI3K/Akt or mTORC1/ p70S6K signaling with different corresponding inhibitors increases the PD-L1 levels in NSCLC and other cancer cell lines expressing basal levels of PD-L1. These data were subsequently confirmed using a genetic approach (e.g., shRNA) [67]. Another recent study showed that simultaneous inhibition of mTOR with temsirolimus and blockade of PD-L1 enhanced CD8+ cytolytic function and tumor suppression in a xenografted mouse model of renal cell carcinoma based on the rationale of mTOR inhibition-induced upregulation of PD-L1 expression [69]
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