• GEO database
• Immunohistochemistry
• Neoadjuvant chemotherapy
• Survival analysis
• Triple-negative breast cancer

• Humans
• Triple Negative Breast Neoplasms/pathology
• Triple Negative Breast Neoplasms/drug therapy
• Triple Negative Breast Neoplasms/genetics
• Triple Negative Breast Neoplasms/metabolism
• Triple Negative Breast Neoplasms/mortality
• Female
• Neoadjuvant Therapy/mortality
• Prognosis
• Middle Aged
• Biomarkers, Tumor/metabolism
• Biomarkers, Tumor/genetics
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Survival Rate
• Follow-Up Studies
• Adult
• Aged
• Gene Expression Regulation, Neoplastic

• No. 2023AH051980, No. 2022AH051479 Key Projects of the Department of Education of Anhui Province
• No. 320.6750.2022-19-79 Clinical research Special Fund of WU JIEPING Medical Foundation
• No. KFDX202203 Open project of Anhui Province Key Laboratory of Cancer Translational Medicine

• Dual-targeting inhibitors
• HDAC6
• Hybrid molecules

• Histone Deacetylase 6/antagonists & inhibitors
• Histone Deacetylase 6/metabolism
• Humans
• Histone Deacetylase Inhibitors/pharmacology
• Histone Deacetylase Inhibitors/chemistry
• Histone Deacetylase Inhibitors/chemical synthesis
• Neoplasms/drug therapy
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/chemistry
• Molecular Structure
• Animals

• Drug delivery
• Niosome
• SAHA
• Suberoylanilide hydroxamic acid, deacetylase inhibitor
• Vesicle
• Zolinza

• Humans
• Vorinostat/pharmacology
• Vorinostat/administration & dosage
• Vorinostat/chemistry
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/administration & dosage
• Antineoplastic Agents/chemistry
• HeLa Cells
• MCF-7 Cells
• Apoptosis/drug effects
• Liposomes
• Hydroxamic Acids/chemistry
• Hydroxamic Acids/administration & dosage
• Hydroxamic Acids/pharmacology
• Drug Carriers/chemistry
• Particle Size
• Nanoparticles/chemistry
• Drug Liberation
• Cell Survival/drug effects

• drug design
• histone deacetylase
• inhibitors
• sophoridine
• triple-negative breast cancer

• Humans
• Histone Deacetylase Inhibitors/pharmacology
• Matrines
• Quinolizidine Alkaloids
• Triple Negative Breast Neoplasms/drug therapy
• Triple Negative Breast Neoplasms/metabolism
• Cell Line, Tumor
• Phosphatidylinositol 3-Kinases/metabolism
• Hydroxamic Acids/pharmacology
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Cell Proliferation
• Histone Deacetylase 1
• Structure-Activity Relationship
• Drug Screening Assays, Antitumor

• 22JCQNJC00320 Natural Science Foundation of Tianjin
• TJSJMYXYC-D2-034 Tianjin High-Level Personnel Training Program

• autophagy
• mTOR
• sophoridine
• triple-negative breast cancer

• Apoptosis
• Autophagy
• HDAC6
• Migration
• TNBC
• mTOR

Hyperactivation of the PI3K/AKT/mTOR cell signalling pathway is an important and well-described mechanism of trastuzumab resistance in HER2-positive breast cancer. In cell-line models of acquired trastuzumab resistance generated in our laboratory, we demonstrate this type of activation, which is independent of HER2-mediated regulation. We investigate whether the use of specific mTOR inhibitors, a PI3K/AKT/mTOR pathway effector, could lead to decreased activity of the pathway, influencing trastuzumab resistance. We demonstrate that TAK-228, a mTORC1 and mTORC2 inhibitor, can reverse resistance and increasing response to trastuzumab in models of primary and acquired resistance.

The use of anti-HER2 therapies has significantly improved clinical outcome in patients with HER2-positive breast cancer, yet a substantial proportion of patients acquire resistance after a period of treatment. The PI3K/AKT/mTOR pathway is a good target for drug development, due to its involvement in HER2-mediated signalling and in the emergence of resistance to anti-HER2 therapies, such as trastuzumab. This study evaluates the activity of three different PI3K/AKT/mTOR inhibitors, i.e., BEZ235, everolimus and TAK-228 in vitro, in a panel of HER2-positive breast cancer cell lines with primary and acquired resistance to trastuzumab. We assess the antiproliferative effect and PI3K/AKT/mTOR inhibitory capability of BEZ235, everolimus and TAK-228 alone, and in combination with trastuzumab. Dual blockade with trastuzumab and TAK-228 was superior in reversing the acquired resistance in all the cell lines. Subsequently, we analyse the effects of TAK-228 in combination with trastuzumab on the cell cycle and found a significant increase in G0/G1 arrest in most cell lines. Likewise, the combination of both drugs induced a significant increase in apoptosis. Collectively, these experiments support the combination of trastuzumab with PI3K/AKT/mTOR inhibitors as a potential strategy for inhibiting the proliferation of HER2-positive breast cancer cell lines that show resistance to trastuzumab.

• PI3K
• TAK-228
• anti-receptor therapy
• breast cancer
• mTOR
• resistance
• trastuzumab

• Cancer
• Copper
• Epigenetics
• Metabolism
• RTK

• PROTAC
• bifunctional inhibitors
• cancer
• histone deacetylase
• histone deacetylase inhibitor

• internal funding Medizinische Fakultät, Universität Leipzig
• #5/19 Roland Ernst Stiftung

It’s well known that the mammalian target of rapamycin (mTOR) exerts a critical role in the regulator of immune cells and is associated with T cells dysfunction in patients with systemic lupus erythematosus (SLE). Antigen-induced T-cell proliferation via mTORC1 suppressed by Rapamycin has been used to improve SLE primarily. Previously it has showed that INK128, a highly potent, specific orally inhibitor of mTORC1 and mTORC2, significantly attenuates SLE in pristine-induced lupus mice. Herein we compared the cure effects of INK128 and rapamycin on lupus mice. We treated MRL/lpr mice with INK128 or rapamycin at 12 weeks-age. The effect of the two inhibitors on the lupus mice was determined by immunohistochemistry. The effect of the two inhibitors on T cell populations was investigated by flow cytometry. The mTOR signaling was measured by Western Blot. INK128 remarkably alleviated SLE by reducing splenomegaly, renal inflammation and damage, and resuming T-cell dysfunction. The more effective of INK128 on SLE than rapamycin. INK128 effectively suppressed mTORC1 and mTORC2 activity in T cells, but rapamycin just suppressed mTORC1 activity. Thus, our results show that INK128 is can effectively alleviate SLE and be used as one of the potential clinical therapeutic candidates for SLE.

• INK128
• SLE
• T cell populations
• mTOR
• rapamycin

• heat shock protein 70
• mammalian target of rapamycin
• microenvironment
• pancreatic ductal adenocarcinoma
• radiofrequency ablation

• Akt
• Breast cancer
• Drug resistance
• Hypoxic conditions
• Protein kinase B
• Targeted therapy

• Cancer
• Epigenetic therapy
• Histone deacetylase (HDAC) Inhibitors
• Histone deacetylases
• Mechanisms
• Signaling pathways.

• preclinical research
• breast cancer
• targeted therapies

• Biomarkers, Tumor/genetics
• Biomarkers, Tumor/metabolism
• Cell Line, Tumor
• Female
• Gene Expression Profiling/methods
• Gene Expression Regulation, Neoplastic
• Gene Regulatory Networks
• Humans
• Middle Aged
• Oligonucleotide Array Sequence Analysis
• Phosphorylation
• Principal Component Analysis
• Prognosis
• Signal Transduction
• Survival Analysis
• Triple Negative Breast Neoplasms/genetics
• Triple Negative Breast Neoplasms/metabolism
• bcl-Associated Death Protein/metabolism

• P30 CA076292 NCI NIH HHS
• R21 CA181617 NCI NIH HHS
• U.S. Department of Health & Human Services | NIH | NCI | Division of Cancer Epidemiology and Genetics, National Cancer Institute (National Cancer Institute Division of Cancer Epidemiology and Genetics)
• U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
• DeBartalo Family Foundation

• proline dehydrogenase (prodh)
• p53-inducible
• n-propargylglycine suicide inhibitor
• glutaminase (gls1) inhibitor
• synthetic lethal interactions

• Animals
• Binding Sites
• Cell Line, Tumor
• Enzyme Activation
• Glutaminase/antagonists & inhibitors
• Glutaminase/chemistry
• Glutaminase/genetics
• Humans
• Mice
• Mitochondria/drug effects
• Mitochondria/genetics
• Mitochondria/metabolism
• Models, Molecular
• Molecular Structure
• Proline Oxidase/antagonists & inhibitors
• Proline Oxidase/chemistry
• Proline Oxidase/genetics
• Protein Binding
• Structure-Activity Relationship
• Synthetic Lethal Mutations
• Transcriptional Activation
• Tumor Suppressor Protein p53/chemistry
• Tumor Suppressor Protein p53/genetics
• Tumor Suppressor Protein p53/metabolism
• Unfolded Protein Response

• K99 AG056680 NIA NIH HHS
• U24 CA143858 NCI NIH HHS

Reversing or slowing the aging process brings great promise to treat or prevent age‐related disease, and targeting the hallmarks of aging is a strategy to achieve this. Epigenetics affects several if not all of the hallmarks of aging and has therefore emerged as a central target for intervention. One component of epigenetic regulation involves histone deacetylases (HDAC), which include the “classical” histone deacetylases (of class I, II, and IV) and sirtuin deacetylases (of class III). While targeting sirtuins for healthy aging has been extensively reviewed elsewhere, this review focuses on pharmacologically inhibiting the classical HDACs to promote health and longevity. We describe the theories of how classical HDAC inhibitors may operate to increase lifespan, supported by studies in model organisms. Furthermore, we explore potential mechanisms of how HDAC inhibitors may have such a strong grasp on health and longevity, summarizing their links to other hallmarks of aging. Finally, we show the wide range of age‐related preclinical disease models, ranging from neurodegeneration to heart disease, diabetes to sarcopenia, which show improvement upon HDAC inhibition.

• HDAC inhibitors
• epigenetics
• geroprotector
• hallmarks of aging
• preclinical models

• HDAC
• cdk
• cell growth
• cyclins
• mtor
• prostate cancer
• resistance
• temsirolimus
• valproic acid

The mammalian or mechanistic target of rapamycin (mTOR) pathway plays a crucial role in regulation of cell survival, metabolism, growth and protein synthesis in response to upstream signals in both normal physiological and pathological conditions, especially in cancer. Aberrant mTOR signaling resulting from genetic alterations from different levels of the signal cascade is commonly observed in various types of cancers. Upon hyperactivation, mTOR signaling promotes cell proliferation and metabolism that contribute to tumor initiation and progression. In addition, mTOR also negatively regulates autophagy via different ways. We discuss mTOR signaling and its key upstream and downstream factors, the specific genetic changes in the mTOR pathway and the inhibitors of mTOR applied as therapeutic strategies in eight solid tumors. Although monotherapy and combination therapy with mTOR inhibitors have been extensively applied in preclinical and clinical trials in various cancer types, innovative therapies with better efficacy and less drug resistance are still in great need, and new biomarkers and deep sequencing technologies will facilitate these mTOR targeting drugs benefit the cancer patients in personalized therapy.

• PI3K
• cancer
• inhibitor
• mTOR
• therapy

• Animals
• Antineoplastic Combined Chemotherapy Protocols/adverse effects
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Biomarkers
• Clinical Trials as Topic
• Humans
• Molecular Targeted Therapy
• Neoplasms/drug therapy
• Neoplasms/metabolism
• Neoplasms/pathology
• Protein Kinase Inhibitors/pharmacology
• Protein Kinase Inhibitors/therapeutic use
• Signal Transduction/drug effects
• TOR Serine-Threonine Kinases/antagonists & inhibitors
• TOR Serine-Threonine Kinases/metabolism
• Treatment Outcome

• AKT
• Breast Cancer
• Clinical Trials
• PI3K
• PI3K/AKT/mTOR pathway
• mTOR

• differentiation
• epigenetics
• mammalian target of rapamycin
• neural stem cells
• valproic acid

Histone deacetylase 5 (HDAC5) is an important protein in neural and cardiac diseases and a potential drug target. However, little is known regarding the specific role of HDAC5 in breast cancer (BC). We aimed to evaluate HDAC5 expression in human breast tumors and to determine the effects of the inhibition of HDAC5 expression in BC cells.

HDAC5 expression was evaluated in BC patients and was correlated with clinical features and with patient prognosis. Functional experiments were performed using shRNA and the selective HDAC inhibitor LMK-235 for HDAC5 knockdown and inhibition in BC cells. The synergistic effects of LMK-235 with the proteasome inhibitor bortezomib were also examined.

HDAC5 was extensively expressed in human BC tissues, and high HDAC5 expression was associated with an inferior prognosis. Knockdown of HDAC5 inhibited cell proliferation, migration, invasion, and enhanced apoptosis. The HDAC5 inhibitor LMK-235 inhibited cell growth and induced apoptosis, while the inclusion of bortezomib synergistically enhanced the efficacy of LMK-235.

Our findings indicate that HDAC5 is a promising prognostic marker and drug target for BC and that the combination of LMK-235 and bortezomib presents a novel therapeutic strategy for BC.

• HDAC inhibitor
• breast cancer
• drug target
• histone deacetylase
• proteasome inhibitor

Loss of 4E-BP1 expression has been linked to cancer progression and resistance to mTOR inhibitors, but the mechanism underlying 4E-BP1 downregulation in tumors remains unclear. Here we identify Snail as a strong transcriptional repressor of 4E-BP1. We find that 4E-BP1 expression inversely correlates with Snail level in cancer cell lines and clinical specimens. Snail binds to three E-boxes present in the human 4E-BP1 promoter to repress transcription of 4E-BP1. Ectopic expression of Snail in cancer cell lines lacking Snail profoundly represses 4E-BP1 expression, promotes cap-dependent translation in polysomes, and reduces the anti-proliferative effect of mTOR kinase inhibitors. Conversely, genetic and pharmacological inhibition of Snail function restores 4E-BP1 expression and sensitizes cancer cells to mTOR kinase inhibitors by enhancing 4E-BP1-mediated translation-repressive effect on cell proliferation and tumor growth. Our study reveals a critical Snail-4E-BP1 signaling axis in tumorigenesis, and provides a rationale for targeting Snail to improve mTOR-targeted therapies.

4E-BP1 is a translational repressor critical in mTOR signaling, whereas Snail is a critical promoter of epithelial to mesenchymal transition. Here the authors show that Snail induces resistance to mTOR inhibitors by repressing 4E-BP1 expression and promoting cell cycle progression via upregulating cycD.

Molecule-targeted therapy has achieved great progress in cancer therapy. Effective drug combinations are one way to enhance the therapeutic efficacy and combat resistance. Here, we determined the effect of the PI3K/mTOR dual inhibitor BEZ235 and the histone deacetylase inhibitor Trichostatin A (TSA) on human breast cancer. We demonstrated that the combination of BEZ235 and TSA results in significant synergistic growth inhibition of multiple breast cancer cell lines. Mechanistic studies revealed that the combined therapy induced apoptosis in a caspase-dependent manner, which might be related to the further depression of the PI3K/Akt/mTOR signalling pathway. Additionally, co-treatment with BEZ235 and TSA enhanced autophagic cell death by up-regulating the expression of LC3B-II and Beclin-1. The vivo tumour modelling studies revealed that BEZ235 combined with TSA blocked tumour growth without noticeable side effects. These data suggest that the combination of BEZ235 and TSA may be a new selective strategy, which may have significant clinical application in the treatment of breast cancer patients.

• BEZ235
• Trichostatin A
• apoptosis
• autophagy
• breast cancer

• Cancer
• Epigenetics
• Receptor tyrosine kinases
• Signal transduction

• PI3K
• breast cancer
• cell signaling
• everolimus
• mTOR
• rapalogues

• Acetazolamide
• Carbonic anhydrases
• HDAC inhibitor
• Histone deacetylases
• MS-275
• Neuroblastoma

• HDAC
• HeLa cells
• Screening
• TSA
• grapeseed
• miRNA

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer. Pathologic activation of PI3K/mTOR pathway and elevated expression of c-Myc are frequently detected in MCC. Yet, there is no targeted therapy presently available for this lethal disease. Recently, MLN0128, a second-generation dual TORC1/2 inhibitor is shown to have therapeutic efficacy in preclinical studies. MLN0128 is currently in clinical trials as a potential therapy for advanced cancers. Here we characterize the therapeutic efficacy of MLN0128 in the preclinical setting of MCC and delineate downstream targets of mTORC1/2 in MCC cellular systems. MLN0128 significantly attenuates xenograft MCC tumor growth independent of Merkel cell polyomavirus. Moreover, MLN0128 markedly diminishes MCC cell proliferation and induces apoptosis. Further investigations indicate that senescence does not contribute to MLN0128-mediated repression of xenograft MCC tumor growth. Finally, we also observe robust antitumor effects of MLN0128 when administered as a dual therapy with JQ1, a bromodomain protein BRD4 inhibitor. These results suggest dual blockade of PI3K/mTOR pathway and c-Myc axis is effective in the control of MCC tumor growth. Our results demonstrate that MLN0128 is potent as monotherapy or as a member of combination therapy with JQ1 for advanced MCC.

• MLN0128
• Merkel cell carcinoma
• mTOR inhibitor
• mTOR pathway

ERα phosphorylation at hinge site S294 (pS294) was recently shown to be essential for ER-dependent gene transcription and mediated by an unknown cyclin-dependent kinase (CDK). This study was undertaken to identify the exact CDK pathway mediating pS294 formation, and to determine if this phosphorylation event occurs with, and can be targeted to treat, the ligand-independent growth of breast cancers expressing endocrine-refractory ESR1 mutations. Using a newly developed anti-pS294 monoclonal antibody, a combination of CDK specific siRNA knockdown studies and a broad panel of CDK selective inhibitors against ligand (E2)-stimulated MCF7 cells, we first identified CDK2 as the primary mediator of pS294 formation and showed that CDK2-selective inhibitors like Dinaciclib, but not CDK4/6 inhibitors like Palbociclib, can selectively prevent pS294 formation and repress ER-dependent gene expression. We then expressed the ER-activating mutations ERmut(Y537S) and ERmut(D538G) in MCF7 cells, and demonstrated their ability to induce ligand-independent and tamoxifen-resistant growth, associated with constitutive and CDK2-dependent pS294 expression. Following robust growth of E2-independent and TAM-resistant MCF7mutER(Y537S) tumors in vivo, nude mice were also treated with either Dinaciclib or Palbociclib at doses and injection schedules unable to retard tumor growth as single agents; the TAM plus Palbociclib combination arrested further tumor growth without affecting pS294 formation, while the TAM plus Dinaciclib combination produced tumor regression associated with loss of pS294 expression. These findings, and our proposed mechanistic model, provide new rationale for the clinical evaluation of CDK2 inhibitors given in combination with endocrine agents as a new treatment strategy against ESR1 mutation expressing breast cancers.

• ERα phosphorylation
• ESR1 mutations
• cyclin-dependent kinase-2 inhibitors

Early detection and improved therapies for many cancers are enhancing survival rates. Although many cytotoxic therapies are approved for aggressive or metastatic cancer; response rates are low and acquisition of de novo resistance is virtually universal. For decades; chemotherapeutic treatments for cancer have included anthracyclines such as Doxorubicin (DOX); and its use in aggressive tumors appears to remain a viable option; but drug resistance arises against DOX; as for all other classes of compounds. Our recent work suggests the anticoagulant protein Tissue Factor Pathway Inhibitor 1α (TFPI1α) plays a role in driving the development of multiple drug resistance (MDR); but not maintenance; of the MDR state. Other factors; such as the ABC transporter drug efflux pumps MDR-1/P-gp (ABCB1) and BCRP (ABCG2); are required for MDR maintenance; as well as development. The patient population struggling with therapeutic resistance specifically requires novel treatment options to resensitize these tumor cells to therapy. In this review we discuss the development, maintenance, and reversal of MDR as three distinct phases of cancer biology. Possible means to exploit these stages to reverse MDR will be explored. Early molecular detection of MDR cancers before clinical failure has the potential to offer new approaches to fighting MDR cancer.

• HIF1
• TFPI
• breast cancer
• hypoxia
• multiple drug resistance/MDR

• Breast cancer
• Cell inhibition
• Estrogen receptors (ER)
• miR-204

• Her2+ BC
• Splice isoforms
• noncanonical

The mevalonate pathway provides metabolites for post-translational modifications such as farnesylation, which are critical for the activity of RAS downstream signaling. Subsequently occurring regulatory processes can induce an aberrant stimulation of DNA methyltransferase (DNMT1) as well as changes in histone deacetylases (HDACs) and microRNAs in many cancer cell lines. Inhibitors of the mevalonate pathway are increasingly recognized as anticancer drugs. Extensive evidence indicates an intense cross-talk between signaling pathways, which affect growth, differentiation, and apoptosis either directly or indirectly via epigenetic mechanisms. Herein, we show data obtained by novel transcriptomic and corresponding methylomic or proteomic analyses from cell lines treated with pharmacologic doses of respective inhibitors (i.e., simvastatin, ibandronate). Metabolic pathways and their epigenetic consequences appear to be affected by a changed concentration of NADPH. Moreover, since the mevalonate metabolism is part of a signaling network, including vitamin D metabolism or fatty acid synthesis, the epigenetic activity of associated pathways is also presented. This emphasizes the far-reaching epigenetic impact of metabolic therapies on cancer cells and provides some explanation for clinical observations, which indicate the anticancer activity of statins and bisphosphonates.

• Mevalonate pathway
• bisphosphonates
• cancer metabolism
• epigenetics
• statins

• Breast cancer
• Chemoresistance
• Microenvironment
• Signaling molecule
• Targeted therapy

• biomarker
• breast cancer
• diet
• epigenetics
• prevention
• prognosis
• treatment

Osteosarcoma (OS) is the most common type of solid bone cancer and remains the second leading cause of cancer-related death for children and young adults. Hypoxia is an element intrinsic to most solid-tumor microenvironments, including that of OS, and is associated with resistance to therapy, poor survival, and a malignant phenotype. Cells respond to hypoxia through alterations in gene expression, mediated most notably through the hypoxia-inducible factor (HIF) class of transcription factors. Here we investigate hypoxia-induced changes in the Wnt/β-catenin signaling pathway, a key signaling cascade involved in OS pathogenesis. We show that hypoxia results in increased expression and signaling activation of HIF proteins in human osteosarcoma cells. Wnt/β-catenin signaling is down-regulated by hypoxia in human OS cells, as demonstrated by decreased active β-catenin protein levels and axin2 mRNA expression (p<0.05). This down-regulation appears to rely on both HIF-independent and HIF-dependent mechanisms, with HIF-1α standing out as an important regulator. Finally, we show that hypoxia results in resistance of human OS cells to doxorubicin-mediated toxicity (6–13 fold increase, p<0.01). These hypoxic OS cells can be sensitized to doxorubicin treatment by further inhibition of the Wnt/β-catenin signaling pathway (p<0.05). These data support the conclusion that Wnt/β-catenin signaling is down-regulated in human OS cells under hypoxia and that this signaling alteration may represent a viable target to combat chemoresistant OS subpopulations in a hypoxic niche.

• Cell Hypoxia
• Cell Line, Tumor
• Down-Regulation
• Doxorubicin/toxicity
• Drug Resistance, Neoplasm
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit/genetics
• Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
• Osteosarcoma/metabolism
• Oxygen/metabolism
• Wnt Signaling Pathway

A characteristic of dysregulated wound healing in IPF is fibroblastic-mediated damage to lung epithelial cells within fibroblastic foci. In these foci, TGF-β and other growth factors activate fibroblasts that secrete growth factors and matrix regulatory proteins, which activate a fibrotic cascade. Our studies and those of others have revealed that Akt is activated in IPF fibroblasts and it mediates the activation by TGF-β of pro-fibrotic pathways. Recent studies show that mTORC2, a component of the mTOR pathway, mediates the activation of Akt. In this study we set out to determine if blocking mTORC2 with MLN0128, an active site dual mTOR inhibitor, which blocks both mTORC1 and mTORC2, inhibits lung fibrosis. We examined the effect of MLN0128 on TGF-β-mediated induction of stromal proteins in IPF lung fibroblasts; also, we looked at its effect on TGF-β-mediated epithelial injury using a Transwell co-culture system. Additionally, we assessed MLN0128 in the murine bleomycin lung model. We found that TGF-β induces the Rictor component of mTORC2 in IPF lung fibroblasts, which led to Akt activation, and that MLN0128 exhibited potent anti-fibrotic activity in vitro and in vivo. Also, we observed that Rictor induction is Akt-mediated. MLN0128 displays multiple anti-fibrotic and lung epithelial-protective activities; it (1) inhibited the expression of pro-fibrotic matrix-regulatory proteins in TGF-β-stimulated IPF fibroblasts; (2) inhibited fibrosis in a murine bleomycin lung model; and (3) protected lung epithelial cells from injury caused by TGF-β-stimulated IPF fibroblasts. Our findings support a role for mTORC2 in the pathogenesis of lung fibrosis and for the potential of active site mTOR inhibitors in the treatment of IPF and other fibrotic lung diseases.

• Animals
• Benzoxazoles/pharmacology
• Bleomycin
• Carrier Proteins/antagonists & inhibitors
• Carrier Proteins/genetics
• Carrier Proteins/metabolism
• Coculture Techniques
• Epithelial Cells/cytology
• Epithelial Cells/drug effects
• Epithelial Cells/metabolism
• Extracellular Matrix Proteins/antagonists & inhibitors
• Extracellular Matrix Proteins/genetics
• Extracellular Matrix Proteins/metabolism
• Fibroblasts/drug effects
• Fibroblasts/metabolism
• Fibroblasts/pathology
• Gene Expression Regulation
• Mechanistic Target of Rapamycin Complex 1
• Mechanistic Target of Rapamycin Complex 2
• Mice
• Multiprotein Complexes/antagonists & inhibitors
• Multiprotein Complexes/genetics
• Multiprotein Complexes/metabolism
• Protective Agents/pharmacology
• Proto-Oncogene Proteins c-akt/antagonists & inhibitors
• Proto-Oncogene Proteins c-akt/genetics
• Proto-Oncogene Proteins c-akt/metabolism
• Pulmonary Fibrosis/chemically induced
• Pulmonary Fibrosis/drug therapy
• Pulmonary Fibrosis/genetics
• Pulmonary Fibrosis/pathology
• Pyrimidines/pharmacology
• Rapamycin-Insensitive Companion of mTOR Protein
• Signal Transduction
• TOR Serine-Threonine Kinases/antagonists & inhibitors
• TOR Serine-Threonine Kinases/genetics
• TOR Serine-Threonine Kinases/metabolism
• Transforming Growth Factor beta/pharmacology