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Inhibiting 4EBP1 in Glioblastoma Qi Wen Fan1,2, Theodore P

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Inhibiting 4EBP1 in Glioblastoma Qi Wen Fan1,2, Theodore P Published OnlineFirst July 10, 2017; DOI: 10.1158/1078-0432.CCR-17-0042 Review Clinical Cancer Research Inhibiting 4EBP1 in Glioblastoma Qi Wen Fan1,2, Theodore P. Nicolaides2,3,4, and William A. Weiss1,2,3,4 Abstract Glioblastoma is the most common and aggressive adult orthosterically with the ATP- and substrate-binding pocket of brain cancer. Tumors show frequent dysregulation of the mTOR kinase, efficiently block 4EBP1 in vitro,andare PI3K–mTOR pathway. Although a number of small molecules currently being investigated in the clinical trials. Preclinical target the PI3K–AKT–mTOR axis, their preclinical and clinical studies suggest that TORKi have poor residence times of mTOR efficacy has been limited. Reasons for treatment failure include kinase, and our data suggest that this poor pharmacology poor penetration of agents into the brain and observations that translates into disappointing efficacy in glioblastoma xeno- blockade of PI3K or AKT minimally affects downstream mTOR grafts. RapaLink-1, a TORKi linked to rapamycin, represents activity in glioma. Clinical trials using allosteric mTOR inhi- a drug with improved pharmacology against 4EBP1. In this bitors (rapamycin and rapalogs) to treat patients with glioblas- review, we clarify the importance of 4EBP1 as a biomarker toma have also been unsuccessful or uncertain, in part, because for the efficacy of PI3K–AKT–mTOR inhibitors in glioblastoma. rapamycin inefficiently blocks the mTORC1 target 4EBP1 and We also review mechanistic data by which RapaLink-1 blocks feeds back to activate PI3K–AKT signaling. Inhibitors of the p-4EBP1 and discuss future clinical strategies for 4EBP1 inhi- mTOR kinase (TORKi) such as TAK-228/MLN0128 interact bition in glioblastoma. Clin Cancer Res; 24(1); 1–8. Ó2017 AACR. Introduction the ribosome and consists of three proteins: (i) eIF4A, an RNA helicase; (ii) eIF4E, a protein that binds and recruits the m7GTP Glioblastoma remains one of the major challenges in pedi- cap of mRNA to the eIF4F complex; and (iii) eIF4G, which serves atric and adult cancer. Despite surgery, radiation, and chemo- a scaffolding function by directly binding to eIF4E, eIF4A, and therapy, patients survive a median of 18 months or less from ribosome-associated eIF3 (6). Interaction of eIF4E with both the diagnosis (1). Glioblastomas frequently activate signaling m7GTP cap and eIF4G is rate limiting in translation. Regulation through PI3K, AKT, and mTOR (2). A number of inhibitors of this step occurs through 4E-binding protein (4EBP), which that target key components of this pathway are being tested binds to eIF4E at the eIF4E–eIF4G interaction interface, to clinically and, to date, have shown limited efficacy (3, 4). prohibit its participation in the initiation complex. Hypophos- mTOR integrates the abundance of nutrients and growth phorylated 4EBP binds eIF4E with high affinity, whereas direct factor to cell growth and metabolism (5). Signaling functions phosphorylation by mTOR causes 4EBP to dissociate from of mTOR are distributed between at least two distinct protein eIF4E. Free eIF4E can then participate in the translation initia- complexes: mTORC1 and mTORC2. In mTORC1, mTOR is tion complex, leading to an increase in cap-dependent transla- associated with proteins including PRAS40 and the rapamy- tion and driving proliferation. cin-sensitive adapter protein of mTOR (Raptor), whereas in How mTORC2 contributes to translation regulation and mTORC2, mTOR is associated with a separate protein complex growth control generally, and in glioblastoma specifically, re- including the rapamycin-insensitive companion of mTOR (Ric- mains less clear (Fig. 1 and ref. 7). This is partly because there tor). The mTORC1 complex signals primarily through two are no specific inhibitors of TORC2. The mTORC2 complex is effectors. One is p70 ribosomal protein S6 kinase (S6K). Phos- stimulated by growth factors that promote PI3K-dependent acti- phorylation and activation of S6K result in phosphorylation of vation of mTORC2. PI3K-independent mechanisms of mTORC2 S6K targets such as eIF4B and ribosomal protein S6 (RPS6). The activation have also been described, and include WNT-LRP5 second major output of mTOR signaling is via regulation of and Notch signaling (8). Activated mTORC2 can phosphorylate the eukaryotic initiation complex eIF4F, which recruits mRNA to several members of the AGC subfamily of kinases, including AKT (Ser 473), SGK1 (Ser 422), PKCa (Ser 657), and the actin cross-linking protein filamin A (FLNA) on Ser 2152, to regulate 1Department of Neurology, University of California, San Francisco, California. tumor growth, metabolism, chemotherapy resistance, and cyto- 2Helen Diller Family Comprehensive Cancer Center, San Francisco, California. skeletal organization in glioblastoma (9, 10). Therefore, 3Department of Pediatrics, University of California, San Francisco, California. mTORC2 may also represent a therapeutic target in glioblastoma. 4 Department of Neurological Surgery, University of California, San Francisco, A number of mTOR inhibitors are currently in preclinical or California. clinical trials for cancer (Table 1; refs. 4, 11–40). Allosteric Corresponding Author: William A. Weiss, University of California, San Francisco, mTOR inhibitors (rapamycin and rapalogs; Fig. 2) bind to 1450 Third Street, Room 277, MC 0520, San Francisco, CA 94158-9001. Phone: FK506 binding protein 12 (FKBP12). The rapamycin–FKBP12 415-502-1694; Fax: 415-476-0133; E-mail: [email protected] complex subsequently binds to a region of mTOR kinase called doi: 10.1158/1078-0432.CCR-17-0042 FK506-rapamycin binding (FRB), outside of the ATP/substrate- Ó2017 American Association for Cancer Research. binding pocket. Binding of FKBP12 and rapamycin to FRB www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2017 American Association for Cancer Research. Published OnlineFirst July 10, 2017; DOI: 10.1158/1078-0432.CCR-17-0042 Fan et al. Growth factor RTK p p p p PIP PIP PDK1 2 3 p PI3K p p Figure 1. PI3K–AKT–mTOR signaling pathways IRS1 PTEN in glioblastoma. S6K negatively affects the insulin–PI3K–AKT pathway as p T308 displayed. This axis is activated in TSC1 response to mTOR blockade (not RHEB AKT shown). Note that our earlier work TSC2 demonstrates that canonical upstream S473 p signaling from AKT to mTOR is not operative in glioblastoma. Activated mTOR mTOR AKT is able to phosphorylate TSC2 without activating mTOR, suggesting that the miswiring may occur at the GβL GβL Raptor Rictor level of TSC1 or RHEB, as displayed. eIF4E, eukaryotic initiation factor 4E; Negative feedback loop feedback Negative mTORC1 mTORC2 IRS1, insulin receptor substrate 1; mTORC1, mTOR complex 1; mTORC2, mTOR complex 2; PDK1, phosphoinositide-dependent kinase 1; α S6K4EBP1 SGK1 PKC PKCa, protein kinase Ca; RHEB, ras homolog enriched in brain; RPS6, ribosomal protein S6; RTK, receptor Cytoskeleton tyrosine kinase; SGK1, glucocorticoid- activation/cellular induced protein kinase 1; S6K, S6 RPS6 el4FE metabolism kinase; TSC1 and TSC2, tuberous sclerosis protein 1 and 2. Translation/ cell proliferation © 2017 American Association for Cancer Research changes the conformation of mTOR allosterically (41), limiting with the ATP-binding pocket of mTOR kinase. As a result, substrate access and resulting in blockade of S6K, but not TORKi block both mTORC1-dependent phosphorylation of 4EBP1. The FRB is not accessible in mTORC2, so rapalogs are 4EBP and S6K, and mTORC2-dependent phosphorylation of mTORC1 selective and inhibitonlyoneoutputofmTORC1 AKT. Although these agents are consequently more active than (42, 43). In addition, rapalogs activate AKT due to a well- rapalogs, this increased activity is due to better inhibition of described negative feedback loop (Fig. 1), potentially reducing mTORC1 rather than to inhibition of mTORC2 (24, 28, 30). their benefit as anticancer agents (44). Indeed, although some The activity of these agents against p-AKT produces a broad- rapalogs have gained FDA approval for the treatment of specific acting agent that may limit the therapeutic index of active site cancers (Table 1), the survival benefitwithrapalogsisonthe inhibitors of mTOR, as mTORC2, but not mTORC1, is essential order of months and not years, likely due, in part, to these drugs for normal cells (49). Also, mTORC2 promotes lipogenesis, having only a cytostatic effect. In lesions driven primarily by glucose uptake, glycolysis, and cell survival through the down- mTORC1 activation, however, rapalogs have shown significant stream targets, such as AKT, serum/glucocorticoid-regulated efficacy. Patients with tuberous sclerosis have germline inacti- kinase (SGK), and protein kinase C (50–52). Because of its vation of either TSC1 or TSC2, which links AKT to mTOR (Fig. role in mediating lipid and glucose homeostasis, blockade of 1), and develop benign growths in multiple organs, including mTORC2 signaling can lead to dose-limiting toxicities related their heart, kidneys, and brain (45). These lesions are extremely to insulin resistance and diabetes. Likely due to mTORC2 sensitive to rapalogs, with everolimus associated with a 75% inhibition, the TORKi Torin 1 is actually more toxic to pan- durable objective response rate in patients with subependymal creatic islet cells than rapamycin (53, 54). giant cell astrocytomas (46), a benign brain tumor found in TORKi such as OSI-027, TAK-228/MLN0128, AZD8055, 15% of patients with tuberous sclerosis. and CC-223 are being tested clinically (Table 1). Although The identification of
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