The Potential Role of mTOR Inhibitors in Non-Small Cell Lung Cancer

Gridelli, Cesare; Maione, Paolo; Rossi, Antonio

doi:10.1634/theoncologist.2007-0171

Cited by 99 publications

(76 citation statements)

References 65 publications

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“…The abnormal hyperactivity of EGFR and its downstream mTOR pathways is the leading cause of resistance to TKIs; furthermore, mTOR inhibitors could effectively control the growth of lung adenocarcinoma even after acquiring resistance to TKIs (13,41,42). In order to further unveil the downstream regulatory molecule mechanisms involved in EGFR/mTOR activation, we simultaneously analyzed mRNA expression of EGFR and DEP-TOR, a naturally occurring inhibitor of mTOR, in tumor tissues of patients with lung adenocarcinoma.…”

Section: Mrna Expression Of Egfr Negatively Correlates With Deptor Inmentioning

confidence: 99%

Reciprocal Negative Regulation between EGFR and DEPTOR Plays an Important Role in the Progression of Lung Adenocarcinoma

Zhou

Guo

et al. 2016

Molecular Cancer Research

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The epidermal growth factor receptor (EGFR) activates downstream mTOR phosphorylation to promote the progression of many different tumor types, thus making it a prime therapeutic target. However, the role of DEP domain-containing mTORinteracting protein (DEPTOR), a natural mTOR inhibitor, remains unclear in this process. Here, it is reported that EGFR expression is significantly increased in tumors of lung adenocarcinoma patients and is negatively correlated with the expression of DEPTOR. Activation of EGFR signaling, by EGF, in A549 lung adenocarcinoma cells (overexpressing EGFR) significantly enhanced the function of the mTOR autoamplification loop, consisting of S6K, mTOR, CK1a, and bTrCP1, which resulted in downregulation of DEPTOR expression. Gefitinib, a specific EGFR inhibitor, stimulated DEPTOR accumulation by downregulating the function of the mTOR autoamplification loop. Furthermore, a series of assays conducted in DEPTOR knockout or ectopic expression in A549 cells confirmed that DEPTOR inhibited proliferation, migration, and invasion as well as the in vivo tumor growth of lung adenocarcinoma. Importantly, tumor progression mediated by EGFR ectopic expression was diminished by transfection with DEPTOR. This study uncovers the important inhibitory role of DEPTOR in lung adenocarcinoma progression and reveals a novel mechanism that EGFR downregulates DEPTOR expression to facilitate tumor growth.Implications: DEPTOR acts as a tumor suppressor by limiting EGFR-driven lung adenocarcinoma progression.

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Section: Mrna Expression Of Egfr Negatively Correlates With Deptor Inmentioning

confidence: 99%

Reciprocal Negative Regulation between EGFR and DEPTOR Plays an Important Role in the Progression of Lung Adenocarcinoma

Zhou

Guo

et al. 2016

Molecular Cancer Research

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“…By measuring 35 S-labeled methionine incorporation into proteins, we estimated global protein synthesis activity in HT1080 cells treated for 4 h with VST, together with 2DG, thapsigargin, or tunicamycin (Fig. 2d).…”

Section: Hypophosphorylation Of 4e-bp1 and Prevention Of Grp78 Inductmentioning

confidence: 99%

Preventing the unfolded protein response via aberrant activation of 4E‐binding protein 1 by versipelostatin

et al. 2009

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We recently isolated a macrocyclic compound, versipelostatin (VST), that exerts in vivo antitumor activity. VST shows unique, selective cytotoxicity to glucose-deprived tumor cells by preventing the unfolded protein response (UPR). Here we show that eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), a negative regulator of eukaryotic initiation factor 4E-mediated protein translation, plays a role in the UPR-inhibitory action of VST. Indeed, 4E-BP1 is aberrantly activated by VST. This activation occurs specifically during glucose deprivation and results in profound translation repression and prevents induction of the typical UPR markers glucose-regulated protein (GRP) 78 and activating transcription factor (ATF) 4. Our overexpression and knockdown experiments showed that 4E-BP1 can regulate GRP78 and ATF4 expression. These mechanisms appear to be specific for VST. By contrast, rapamycin, which activates 4E-BP1 regardless of cellular glucose availability, has only marginal effects on the expression of GRP78 and ATF4. Our present findings demonstrate that aberrant 4E-BP1 activation can contribute to UPR preventing by VST, possibly through a mechanism that does not operate in rapamycin-treated cells. (Cancer Sci 2009; 100: 327-333) S olid tumors have regions of low glucose and low oxygen (hypoxia) that arise from immature and irregular distribution of microvasculature.(1,2) In this stressful microenvironment, tumor cells are thought to survive by activating adaptive response pathways.(3) An important response for tumor development is the unfolded protein response (UPR), which can be activated in tumor cells during glucose deprivation as well as hypoxia.(4,5) The UPR has also been associated with lowered chemosensitivity in breast cancer and gliomas. (6,7) The UPR is a regulatory network that allows the cells to cope with stress that leads to the accumulation of misfolded or unfolded proteins in the endoplasmic reticulum (ER).(8) The main signaling pathways are sensed and initiated by the ERlocalized transmembrane proteins Double-standard RNA-dependent Protein Kinase (PKR)-like ER kinase (PERK), inositol-requiring 1 (IRE1), and activating transcription factor (ATF) 6.(8) These signaling pathways reduce global translation and produce several different active transcription factors to induce divergent UPR target genes, such as the ER-resident molecular chaperones glucose-regulated protein (GRP) 78 and GRP94. (5,8,9) Thus, during the UPR, both translational and transcriptional control mechanisms operate to relieve ER stress to allow for cell survival. (9)(10)(11)(12) In the case of intolerable levels of ER stress, however, the sensor proteins can contribute to apoptosis. (9)(10)(11)(12)(13) In the UPR translational control, PERK plays a major role by phosphorylating eukaryotic initiation factor (eIF) 2α at Ser51. (12,14) Phosphorylation of eIF2α reduces global translation and, paradoxically, directs preferential translation of ATF4, a UPR transcription activator.(15) The signaling pathway is further regulated by...

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“…The crucial role of the constitutive activation of the PI3K/AKT pathway in the development and maintenance of an EGFR-resistant phenotype supports the hypothesis that a combination of EGFR TKIs and mTOR inhibitors may be the best choice for treatment. Clinical trials testing this strategy in advanced NSCLC are ongoing and only preliminary results are available [18][19][20]. …”

Section: Introductionmentioning

confidence: 99%

Everolimus restores gefitinib sensitivity in resistant non-small cell lung cancer cell lines

Monica

Galetti

Alfieri

et al. 2009

Biochemical Pharmacology

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 2 ABSTRACTThe epidermal growth factor receptor (EGFR) is a validated target for therapy in non-small cell lung cancer (NSCLC). Most patients, however, either do not benefit or develop resistance to specific inhibitors of the EGFR tyrosine kinase activity, such as gefitinib or erlotinib. The mammalian target of rapamycin (mTOR) is a key intracellular kinase integrating proliferation and survival pathways and has been associated with resistance to EGFR tyrosine kinase inhibitors. In this study, we assessed the effects of combining the mTOR inhibitor everolimus (RAD001) with gefitinib on a panel of NSCLC cell lines characterized by gefitinib-resistance and able to maintain pS6K phosphorylation after gefitinib treatment.Everolimus plus gefitinib induced a significant decrease in the activation of MAPK and mTOR signaling pathways downstream of EGFR and resulted in a growth-inhibitory effect rather than in an enhancement of cell death. A synergistic effect was observed in those cell lines characterized by high proliferative index and low doubling time. These data suggest that treatment with everolimus and gefitinib might be of value in the treatment of selected NSCLC patients that exhibit high tumor proliferative activity.

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The Potential Role of mTOR Inhibitors in Non-Small Cell Lung Cancer

Cited by 99 publications

References 65 publications

Reciprocal Negative Regulation between EGFR and DEPTOR Plays an Important Role in the Progression of Lung Adenocarcinoma

Reciprocal Negative Regulation between EGFR and DEPTOR Plays an Important Role in the Progression of Lung Adenocarcinoma

Preventing the unfolded protein response via aberrant activation of 4E‐binding protein 1 by versipelostatin

Everolimus restores gefitinib sensitivity in resistant non-small cell lung cancer cell lines

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