Combined CDK4/6 and mTOR Inhibition Is Synergistic against Glioblastoma via Multiple Mechanisms

Olmez, Inan; Brenneman, Breanna; Xiao, Aizhen; Serbulea, Vlad; Benamar, Mouadh; Zhang, Ying; Manigat, Laryssa; Abbas, Tarek; Lee, Jeongwu; Nakano, ﻿Ichiro; Godlewski, Jakub; Bronisz, Agnieszka; Abounader, Roger; Leitinger, Norbert; Purow, Benjamin

doi:10.1158/1078-0432.ccr-17-0803

Cited by 78 publications

(78 citation statements)

References 47 publications

(56 reference statements)

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“…These findings shed further light on the cell cycle-dependent phosphorylation of 4E-BP1, the regulation of which was previously reported to be mediated by CDK1 and CDK12 in mitotic cells [29,61,62], and PLK1 and CDK1 in cells undergoing meiosis [22,32,[63][64][65]. Given this newly discovered role of CDK4, it is likely that inhibition of mitotic 4E-BP1 phosphorylation is a previously unknown function of CDK4/6 inhibitors such as palbociclib, and may explain the synergy between these drugs and mTOR inhibitors [66][67][68][69][70][71][72]. It is important to try to reconcile these observations with those previously observed that report CDK1 as the principal kinase that phosphorylates 4E-BP1 during mitosis [30,33].…”

Section: Discussionmentioning

confidence: 77%

Cyclin‐dependent kinase 4 inhibits the translational repressor 4E‐BP1 to promote cap‐dependent translation during mitosis–G1 transition

2019

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Phosphorylation of translational repressor eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) controls the initiation of capdependent translation, a type of protein synthesis that is frequently upregulated in human diseases such as cancer. Because of its critical cellular function, it is not surprising that multiple kinases can post-translationally modify 4E-BP1 to drive aberrant cap-dependent translation. We recently reported a site-selective chemoproteomic method for uncovering kinase-substrate interactions, and using this approach, we discovered the cyclin-dependent kinase (CDK)4 as a new 4E-BP1 kinase. Herein, we describe our extension of this work and reveal the role of CDK4 in modulating 4E-BP1 activity in the transition from mitosis to G1, thereby demonstrating a novel role for this kinase in cell cycle regulation.Cap-dependent translation is an important cellular process that controls the translation of select mRNAs typically encoding for growth factors and oncogenes [1][2][3][4]. The initiation of cap-dependent mRNA translation is governed by the availability of eIF4E, the m 7 GpppX-cap-binding translation initiation factor [5,6]. This protein is highly regulated, primarily through the work of the 4E-BPs, which sequester eIF4E from eIF4G and the eIF4F translation initiation complex [7][8][9][10][11][12][13]. The activity of 4E-binding protein 1 (4E-BP1) is in turn regulated by phosphorylation, where hypophosphorylated 4E-BP1 binds strongly to eIF4E to inhibit translation, while hyperphosphorylated 4E-BP1 releases eIF4E to initiate capdependent translation [13][14][15][16]. For many years, the only validated kinase known to affect 4E-BP1 phosphorylation has been mechanistic target of rapamycin complex 1 (mTORC1), which was shown to hierarchically phosphorylate 4E-BP1 at T37 and T46 followed by T70 and S65 [14,15,17,18]. However, several findings have called into question the exclusivity of mTORC1 for each of these phosphorylation sites [19], namely reports demonstrating that other unknown kinases can also phosphorylate 4E-BP1 to stimulate cap-dependent translation [20][21][22], particularly in cases of mTOR inhibitor drug resistance [23][24][25][26].Recently, our laboratory has developed a chemoproteomic pipeline by which to identify site-specific kinase-substrate interactions, Phosphosite-Accurate kinase-substrate cross(X)linking Assay or PhAXA [27]. Using this methodology, we discovered that cyclin-dependent kinase 4 (CDK4), which is primarily responsible for controlling the cell cycle checkpoint at the G 1 /S transition through phosphorylation of the retinoblastoma tumor suppressor protein (Rb) Abbreviations 4E-BP1, 4E-binding protein 1; CDK, cyclin-dependent kinase; FDR, false discovery rate; mTORC1, mechanistic target of rapamycin complex 1; PSMs, peptide-spectrum matches; WT, wild-type.

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Section: Discussionmentioning

confidence: 77%

Cyclin‐dependent kinase 4 inhibits the translational repressor 4E‐BP1 to promote cap‐dependent translation during mitosis–G1 transition

2019

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“…Finally, some review articles, analyzing alterations in the PI3K/AKT/mTOR pathway in ER+ breast tumors associated with endocrine therapy resistance, where selected. (Olmez et al, 2017).…”

Section: Target Therapy: Cdk 4/6 Inhibitorsmentioning

confidence: 99%

Sequential or Concomitant Inhibition of Cyclin-Dependent Kinase 4/6 Before mTOR Pathway in Hormone-Positive HER2 Negative Breast Cancer: Biological Insights and Clinical Implications

Occhipinti¹,

Romagnoli

Santoni

et al. 2020

Front. Genet.

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About 75% of all breast cancers are hormone receptor-positive (HR+). However, the efficacy of endocrine therapy is limited due to the high rate of either pre-existing or acquired resistance. In this work we reconstructed the pathways around estrogen receptor (ER), mTOR, and cyclin D in order to compare the effects of CDK4/6 and PI3K/AKT/mTOR inhibitors. A positive feedback loop links mTOR and ER that support each other. We subsequently considered whether a combined or sequential inhibition of CDK4/6 and PI3K/AKT/mTOR could ensure better results. Studies indicate that inhibition of CDK4/6 activates mTOR as an escape mechanism to ensure cell proliferation. In literature, the little evidence dealing with this topic suggests that pretreatment with mTOR pathway inhibitors could prevent or delay the onset of CDK4/6 inhibitor resistance. Additional studies are needed in order to find biomarkers that can identify patients who will develop this resistance and in whom the sensitivity to CDK4/6 inhibitors can be restored.

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“…Meclizine and flunarizine were more toxic than rapamycin ( Figure 3). Rapamycin has been used in multiple GBM clinical trials (21)(22)(23)(24).…”

Section: Piperazine Drugs Kill Gbmscsmentioning

confidence: 99%

“…Flunarizine reduced GBMSC viability to a similar extent ( Fig.4). Both meclizine and flunarizine were significantly more toxic to GBMSCs than rapamycin, a drug that has been used in several GBM clinical trials (21)(22)(23)(24). The IC50's for meclizine, flunarizine, and rapamycin are 5.3µM, 6.8µM, and 14µM respectively.…”

Section: Comparison Of Gbm Cell Viability After Treatment With Meclizmentioning

confidence: 99%

Novel mTORC1 inhibitors kill Glioblastoma stem cells

Sandoval

Tomilov

Datta

et al. 2020

Preprint

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Glioblastoma Multiforme (GBM) is an aggressive tumor of the brain, with an average post-diagnosis survival of 15 months. GBM stem cells (GBMSC) resist the standard-of-care therapy, temozolomide, and are considered a major contributor to tumor resistance. mTORC1 regulates cell proliferation and has been shown by others to have reduced activity in GBMSC.We recently identified a novel chemical series of human-safe piperazine-based brain-penetrant mTORC1-specific inhibitors. We assayed piperazine-mTOR binding strength by two biophysical measurements--biolayer interferometry and field effect biosensing, and these confirmed each other and demonstrated a structure-activity relationship. Since mTORC1 is reduced in human GBMSC, and as mTORC1 inhibitors have been tested in previous GBM clinical trials, we tested the killing potency of the tightest-binding piperazines and observed these were potent GBMSC killers. GBMSCs are resistant to the standard-of-care temozolomide therapy--but temozolomide supplemented with tight-binding piperazine meclizine and flunarizine greatly enhanced GBMSC death over temozolomide alone. Lastly, we investigated IDH1-mutated GBMSC mutations that are known to affect mitochondrial and mTORC1 metabolism, the tight-binding Meclizine provoked 'synthetic lethality' in IDH1-mutant GBMSCs. These data tend to support a novel clinical strategy for GBM, i.e. the co-administration of meclizine or flunarizine as adjuvant therapy in the treatment of GBM, and IDH1-mutant GBM.

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Combined CDK4/6 and mTOR Inhibition Is Synergistic against Glioblastoma via Multiple Mechanisms

Cited by 78 publications

References 47 publications

Cyclin‐dependent kinase 4 inhibits the translational repressor 4E‐BP1 to promote cap‐dependent translation during mitosis–G1 transition

Cyclin‐dependent kinase 4 inhibits the translational repressor 4E‐BP1 to promote cap‐dependent translation during mitosis–G1 transition

Sequential or Concomitant Inhibition of Cyclin-Dependent Kinase 4/6 Before mTOR Pathway in Hormone-Positive HER2 Negative Breast Cancer: Biological Insights and Clinical Implications

Novel mTORC1 inhibitors kill Glioblastoma stem cells

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