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Adaptive responses to mTOR gene targeting in hematopoietic stem cells reveal a proliferative mechanism evasive to mTOR inhibition.

ABSTRACT: The mechanistic target of rapamycin (mTOR) is a central regulator of cell growth and an attractive anticancer target that integrates diverse signals to control cell proliferation. Previous studies using mTOR inhibitors have shown that mTOR targeting suppresses gene expression and cell proliferation. To date, however, mTOR-targeted therapies in cancer have seen limited efficacy, and one key issue is related to the development of evasive resistance. In this manuscript, through the use of a gene targeting mouse model, we have found that inducible deletion of mTOR in hematopoietic stem cells (HSCs) results in a loss of quiescence and increased proliferation. Adaptive to the mTOR loss, mTOR ^-/- HSCs increase chromatin accessibility and activate global gene expression, contrary to the effects of short-term inhibition by mTOR inhibitors. Mechanistically, such genomic changes are due to a rewiring and adaptive activation of the ERK/MNK/eIF4E signaling pathway that enhances the protein translation of RNA polymerase II, which in turn leads to increased c-Myc gene expression, allowing the HSCs to thrive despite the loss of a functional mTOR pathway. This adaptive mechanism can also be utilized by leukemia cells undergoing long-term mTOR inhibitor treatment to confer resistance to mTOR drug targeting. The resistance can be counteracted by MNK, CDK9, or c-Myc inhibition. These results provide insights into the physiological role of mTOR in mammalian stem cell regulation and implicate a mechanism of evasive resistance in the context of mTOR targeting.

SUBMITTER: Fan C

PROVIDER: S-EPMC7817152 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Adaptive responses to mTOR gene targeting in hematopoietic stem cells reveal a proliferative mechanism evasive to mTOR inhibition

Project description:The mechanistic target of rapamycin (mTOR) is a central regulator of cell growth and an attractive anti-cancer target that integrates diverse signals to control cell proliferation. Previous studies using mTOR inhibitors have shown that mTOR targeting suppresses gene expression and cell proliferation. To date, however, mTOR targeted therapies in cancer have seen very limited efficacy, and one key issue is related to the development of evasive resistance. In this manuscript, through the use of a gene targeting mouse model, we have found that inducible deletion of mTOR in hematopoietic stem cells (HSCs) results in a loss of quiescence and increased proliferation. Adaptive to the mTOR loss, mTOR-/- HSCs increase chromatin accessibility and activate global gene expression, contrary to the effects of short-term inhibition by mTOR inhibitors. Mechanistically, such genomic changes are due to a rewiring and adaptive activation of the ERK/MNK/eIF4E signaling pathway that enhances the protein translation of RNA polymerase II (RNAP II), which in turn leads to increased c-Myc gene expression, allowing the HSCs to thrive despite loss of a functional mTOR pathway. This adaptive mechanism can also be utilized by leukemia cells undergoing long-term mTOR inhibitor treatment to confer resistance to mTOR drug targeting. The resistance can then be counteracted by MNK, CDK9, or c-Myc inhibition. These results provide new insights into the physiological role of mTOR in mammalian stem cell regulation and implicate a novel mechanism of evasive resistance in the context of mTOR targeting.

2020-12-24 | GSE134316 | GEO

Adaptive responses to mTOR gene targeting in hematopoietic stem cells reveal a proliferative mechanism evasive to mTOR inhibition

Project description:Adaptive responses to mTOR gene targeting in hematopoietic stem cells reveal a proliferative mechanism evasive to mTOR inhibition

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Adaptive responses to mTOR targeting sustain hematopoietic and leukemia stem cell proliferation II

Project description:mTOR is an important anti-cancer target that integrates diverse signals to control protein synthesis and cell growth. Numerous studies by using mTOR inhibitors and/or gene deletion of mTOR negative regulators have implicated mTOR targeting in suppressing gene expression and cell proliferation. However, we found that gene targeting of mTOR in mouse hematopoietic stem cells (HSCs) results in a loss of quiescence and increased proliferation. Adaptive to mTOR loss, mTOR-/- HSCs increase chromatin access and activate global gene expression, in contrast to short-term inhibition by mTOR inhibitors. Such genomic changes are due to a compensatory activation of a MAPK/Mnk/eIF4E signaling pathway that enhances the translation of RNA pol-II and consequent c-myc expression. This adaptive mechanism can also be adopted by leukemia stem cells undergone long-term mTOR inhibitor treatment to confer resistant to mTOR targeting. Our studies provide new insights and a foregone strategy for overcoming drug resistance in mTOR targeted therapy.

2020-12-24 | GSE134317 | GEO

Epigenetic inhibition of adaptive bypass responses to lapatinib by targeting BET Bromodomains.

Project description:The characterization of kinases as oncogenic drivers has led to more than 30 FDA-approved targeted kinase inhibitors for cancer treatment. Unfortunately, these therapeutics fail to have clinical durability because of adaptive responses from the kinome and transcriptome that bypass inhibition of the targeted pathway. In our recent work, we describe a method to prevent these adaptive responses at an epigenetic level, generating a durable response to kinase inhibition.

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Adaptive responses to mTOR targeting sustain hematopoietic and leukemia stem cell proliferation II

Project description:Adaptive responses to mTOR targeting sustain hematopoietic and leukemia stem cell proliferation II

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Small Molecule Inhibition of miR-544 Biogenesis Disrupts Adaptive Responses to Hypoxia by Modulating ATM-mTOR Signaling.

Project description:Hypoxia induces a complex circuit of gene expression that drives tumor progression and increases drug resistance. Defining these changes allows for an understanding of how hypoxia alters tumor biology and informs design of lead therapeutics. We probed the role of microRNA-544 (miR-544), which silences mammalian target of rapamycin (mTOR), in a hypoxic breast cancer model by using a small molecule (1) that selectively impedes the microRNA's biogenesis. Application of 1 to hypoxic tumor cells selectively inhibited production of the mature microRNA, sensitized cells to 5-fluorouracil, and derepressed mRNAs affected by miR-544 in cellulo and in vivo, including boosting mTOR expression. Thus, small molecule inhibition of miR-544 reverses a tumor cell's physiological response to hypoxia. Importantly, 1 sensitized tumor cells to hypoxia-associated apoptosis at a 25-fold lower concentration than a 2'-O-methyl RNA antagomir and was as selective. Further, the apoptotic effect of 1 was suppressed by treatment of cell with rapamycin, a well-known inhibitor of the mTOR signaling pathway, illustrating the selectivity of the compound. Thus, RNA-directed chemical probes, which could also serve as lead therapeutics, enable interrogation of complex cellular networks in cells and animals.

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Personalized Proteomics in Proliferative Vitreoretinopathy Implicate Hematopoietic Cell Recruitment and mTOR as a Therapeutic Target.

Project description:PURPOSE:To profile vitreous cytokine expression of proliferative vitreoretinopathy (PVR) patients. DESIGN:Case-control study. METHODS:Liquid biopsies were collected from 2 groups: control subjects (n = 3) undergoing pars plana vitrectomy to remove an epiretinal membrane (ERM), and test subjects (n = 7) with varying degrees of PVR. A high-throughput cytokine screen measured expression of 200 cytokines. Cytokine expression patterns were prospectively validated in separate cohorts of control patients and those with PVR-A, PVR-B, and PVR-C (n = 10 for each group). Expression changes were evaluated by analysis of variance (significant P value < .05), hierarchical cluster algorithm, and pathway analysis, to identify candidate pathways for prospective studies. RESULTS:In PVR vitreous, 29 cytokines were upregulated compared to controls. Early PVR vitreous showed upregulation of T-cell markers, profibrotic cytokines, and cytokines downstream of mTOR activation (IL-2, IL-6, and IL-13), whereas in late PVR vitreous, cytokines driving monocyte responses and stem-cell recruitment (SDF-1) prevailed. Prospective validation confirmed the differential expression of specific cytokines from PVR-A to C. CONCLUSIONS:Early PVR is characterized by activation of T cells and mTOR signaling, whereas advanced PVR is characterized by a chronic monocyte response. PVR might be treated by rational repositioning of existing drugs that target mTOR and IL-6. Our analysis demonstrates that successful therapeutic intervention will be highly dependent on the specific therapeutic target and the stage of PVR. This study provides insights into cytokines that will serve as biomarkers and therapeutic targets. These biomarkers will help design clinical trials that intervene at appropriate times.

| S-EPMC5805631 | biostudies-literature

Senescence is a Spi1-induced anti-proliferative mechanism in primary hematopoietic cells.

Project description:Transcriptional deregulation caused by epigenetic or genetic alterations is a major cause of leukemic transformation. The Spi1/PU.1 transcription factor is a key regulator of many steps of hematopoiesis, and limits self-renewal of hematopoietic stem cells. The deregulation of its expression or activity contributes to leukemia, in which Spi1 can be either an oncogene or a tumor suppressor. Herein we explored whether cellular senescence, an anti-tumoral pathway that restrains cell proliferation, is a mechanism by which Spi1 limits hematopoietic cell expansion, and thus prevents the development of leukemia. We show that Spi1 overexpression triggers cellular senescence both in primary fibroblasts and hematopoietic cells. Erythroid and myeloid lineages are both prone to Spi1-induced senescence. In hematopoietic cells, Spi1-induced senescence requires its DNA-binding activity and a functional p38MAPK14 pathway but is independent of a DNA-damage response. In contrast, in fibroblasts, Spi1-induced senescence is triggered by a DNA-damage response. Importantly, using our well-established Spi1 transgenic leukemia mouse model, we demonstrate that Spi1 overexpression also induces senescence in erythroid progenitors of the bone marrow in vivo before the onset of the pre-leukemic phase of erythroleukemia. Remarkably, the senescence response is lost during the progression of the disease and erythroid blasts do not display a higher expression of Dec1 and CDKN1A, two of the induced senescence markers in young animals. These results bring indirect evidence that leukemia develops from cells which have bypassed Spi1-induced senescence. Overall, our results reveal senescence as a Spi1-induced anti-proliferative mechanism that may be a safeguard against the development of acute myeloid leukemia.

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Dual inhibition of PI3K and mTOR inhibits autocrine and paracrine proliferative loops in PI3K/Akt/mTOR-addicted lymphomas.

Project description:Primary effusion lymphoma (PEL) constitutes a subset of non-Hodgkin lymphoma whose incidence is highly increased in the context of HIV infection. Kaposi sarcoma-associated herpesvirus is the causative agent of PEL. The phosphatidylinositol 3-kinase (PI3K) signaling pathway plays a critical role in cell proliferation and survival, and this pathway is dysregulated in many different cancers, including PEL, which display activated PI3K, Akt, and mammalian target of rapamycin (mTOR) kinases. PELs rely heavily on PI3K/Akt/mTOR signaling, are dependent on autocrine and paracrine growth factors, and also have a poor prognosis with reported median survival times of less than 6 months. We compared different compounds that inhibit the PI3K/Akt/mTOR pathway in PEL. Although compounds that modulated activity of only a single pathway member inhibited PEL proliferation, the use of a novel compound, NVP-BEZ235, that dually inhibits both PI3K and mTOR kinases was significantly more efficacious in culture and in a PEL xenograft tumor model. NVP-BEZ235 was effective at low nanomolar concentrations and has oral bioavailability. We also report a novel mechanism for NVP-BEZ235 involving the suppression of multiple autocrine and paracrine growth factors required for lymphoma survival. Our data have broad applicability for the treatment of cytokine-dependent tumors with PI3K/mTOR dual inhibitors.

| S-EPMC2881502 | biostudies-literature

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Project description:Abnormal activation of the mammalian target of rapamycin (mTOR) signaling pathway has been observed in a variety of human cancers. Therefore, targeting of the mTOR pathway is an attractive strategy for cancer treatment and several mTOR inhibitors, including AZD8055 (AZD), a novel dual mTORC1/2 inhibitor, are currently in clinical trials. Although bone marrow (BM) suppression is one of the primary side effects of anticancer drugs, it is not known if pharmacological inhibition of dual mTORC1/2 affects BM hematopoietic stem and progenitor cells (HSPCs) function and plasticity. Here we report that dual inhibition of mTORC1/2 by AZD or its analogue (KU-63794) depletes mouse BM Lin(-)Sca-1(+)c-Kit(+) cells in cultures via the induction of apoptotic cell death. Subsequent colony-forming unit (CFU) assays revealed that inhibition of mTORC1/2 suppresses the clonogenic function of hematopoietic progenitor cells (HPCs) in a dose-dependent manner. Surprisingly, we found that dual inhibition of mTORC1/2 markedly inhibits the growth of day-14 cobblestone area-forming cells (CAFCs) but enhances the generation of day-35 CAFCs. Given the fact that day-14 and day-35 CAFCs are functional surrogates of HPCs and hematopoietic stem cells (HSCs), respectively, these results suggest that dual inhibition of mTORC1/2 may have distinct effects on HPCs versus HSCs.

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