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Project description:mTOR is a serine/threonine kinase with a crucial role in regulating fundamental cellular processes and is an attractive anticancer target. Multiple clinical trials of mTOR kinase inhibitors such as AZD2014 that suppress both mTORC1 and mTORC2 are ongoing, but their specificity and toxicity features remain a concern. We have developed an inducible kinase-dead D2338A mTOR mouse knock-in model and show that it is useful to study the kinase-independent function of mTOR and for assessing the off-target effects of mTOR kinase inhibitors. We found that while the mTOR KI mice in hematopoietic system displayed similar phenotypes to that of mTOR KO mice, they have significantly prolonged survival time than the KO mice. Whereas AZD2014 was mostly on-target in suppressing mTOR kinase activity, mimicking that seen in KI stem cells in transcriptome analysis, off-target genes in KI cells induced by AZD2014 including Ahnak2, Emp1, Lilrb4, Tpsb2, and Cma1 were detected. Our studies reveal kinase-independent function of mTOR in hematopoiesis and presents a mouse model for precisely assessing specificity of mTOR kinase inhibitors. Stringent test of drugs with such mouse models in the preclinical setting may provide useful information guiding the safety and efficacy of related clinical trials.
2023-08-29 | GSE172248 | GEO
Project description:mTOR is a serine/threonine kinase with a crucial role in regulating fundamental cellular processes and is an attractive anticancer target. Multiple clinical trials of mTOR kinase inhibitors such as AZD2014 that suppress both mTORC1 and mTORC2 are ongoing, but their specificity and toxicity features remain a concern. We have developed an inducible kinase-dead D2338A mTOR mouse knock-in model and show that it is useful to study the kinase-independent function of mTOR and for assessing the off-target effects of mTOR kinase inhibitors. We found that while the mTOR KI mice in hematopoietic system displayed similar phenotypes to that of mTOR KO mice, they have significantly prolonged survival time than the KO mice. Whereas AZD2014 was mostly on-target in suppressing mTOR kinase activity, mimicking that seen in KI stem cells in transcriptome analysis, off-target genes in KI cells induced by AZD2014 including Ahnak2, Emp1, Lilrb4, Tpsb2, and Cma1 were detected. Our studies reveal kinase-independent function of mTOR in hematopoiesis and presents a mouse model for precisely assessing specificity of mTOR kinase inhibitors. Stringent test of drugs with such mouse models in the preclinical setting may provide useful information guiding the safety and efficacy of related clinical trials.
2023-08-30 | GSE172247 | GEO
Project description:mTOR is a serine/threonine kinase with a crucial role in regulating fundamental cellular processes and is an attractive anticancer target. Multiple clinical trials of mTOR kinase inhibitors such as AZD2014 that suppress both mTORC1 and mTORC2 are ongoing, but their specificity and toxicity features remain a concern. We have developed an inducible kinase-dead D2338A mTOR mouse knock-in model and show that it is useful to study the kinase-independent function of mTOR and for assessing the off-target effects of mTOR kinase inhibitors. We found that while the mTOR KI mice in hematopoietic system displayed similar phenotypes to that of mTOR KO mice, they have significantly prolonged survival time than the KO mice. Whereas AZD2014 was mostly on-target in suppressing mTOR kinase activity, mimicking that seen in KI stem cells in transcriptome analysis, off-target genes in KI cells induced by AZD2014 including Ahnak2, Emp1, Lilrb4, Tpsb2, and Cma1 were detected. Our studies reveal kinase-independent function of mTOR in hematopoiesis and presents a mouse model for precisely assessing specificity of mTOR kinase inhibitors. Stringent test of drugs with such mouse models in the preclinical setting may provide useful information guiding the safety and efficacy of related clinical trials.
2023-08-29 | GSE235097 | GEO
Project description:A mouse model for assessing mTOR kinase-independent role and off-target effect of mTOR kinase inhibitors
| PRJNA722518 | ENA
Project description:A mouse model for assessing mTOR kinase-independent role and off-target effect of mTOR kinase inhibitors [II]
| PRJNA722522 | ENA
Project description:A mouse model for assessing mTOR kinase-independent role and off-target effect of mTOR kinase inhibitors [I]
| PRJNA722519 | ENA
Project description:A mouse model for assessing mTOR kinase-independent role and off-target effect of mTOR kinase inhibitors [III]
| PRJNA984322 | ENA
Project description:Radiotherapy is routinely used as a neoadjuvant, adjuvant or palliative treatment in various cancers. There is significant variation in clinical response to radiotherapy with or without traditional chemotherapy. Patients with a good response to radiotherapy demonstrate better clinical outcomes universally across different cancers. The PI3K/AKT/mTOR pathway upregulation has been linked to radiotherapy resistance. We reviewed the current literature exploring the role of inhibiting targets along this pathway, in enhancing radiotherapy response. We identified several studies using in vitro cancer cell lines, in vivo tumour xenografts and a few Phase I/II clinical trials. Most of the current evidence in this area comes from glioblastoma multiforme, non-small cell lung cancer, head and neck cancer, colorectal cancer, and prostate cancer. The biological basis for radiosensitivity following pathway inhibition was through inhibited DNA double strand break repair, inhibited cell proliferation, enhanced apoptosis and autophagy as well as tumour microenvironment changes. Dual PI3K/mTOR inhibition consistently demonstrated radiosensitisation of all types of cancer cells. Single pathway component inhibitors and other inhibitor combinations yielded variable outcomes especially within early clinical trials. There is ample evidence from preclinical studies to suggest that direct pharmacological inhibition of the PI3K/AKT/mTOR pathway components can radiosensitise different types of cancer cells. We recommend that future in vitro and in vivo research in this field should focus on dual PI3K/mTOR inhibitors. Early clinical trials are needed to assess the feasibility and efficacy of these dual inhibitors in combination with radiotherapy in brain, lung, head and neck, breast, prostate and rectal cancer patients.
| S-EPMC7281073 | biostudies-literature
Project description:FLT3-ITD tyrosine kinase inhibitors (TKI) show limited clinical activity in acute myeloid leukemia (AML) due to emerging resistance. TKI resistance is mediated by secondary FLT3-ITD mutations only in a minority of cases. We hypothesize that the cytokine CCL5 protects AML cells from TKI-mediated cell death and contributes to treatment resistance. We generated PKC412- and sorafenib-resistant MOLM-13 cell lines as an in vitro model to study TKI resistance in AML. Increased CCL5 levels were detected in supernatants from PKC412-resistant cell lines compared to TKI-sensitive cells. Moreover, CCL5 treatment of TKI-sensitive cells induced resistance to PKC412. In resistant cell lines with high CCL5 release, we observed a significant downregulation of the CCL5-receptor CCR5 and CXCR4. In these cell lines, TKI resistance could be partly overcome by addition of the CXCR4-receptor antagonist plerixafor. Microarray and intracellular flow cytometry analyses revealed increased p-Akt or p-Stat5 levels in PKC412-resistant cell lines releasing high amounts of CCL5. Treatment with the CXCR4 antagonist plerixafor, αCCL5, or CCR5-targeting siRNA led to a decrease of p-Akt-positive cells. Transient transfection of sensitive MOLM-13 cells with a CCL5-encoding vector mediated resistance against PKC412 and led to an increase in p-Akt-positive and p-Stat5-positive cells. Isolated AML blasts from patients treated with PKC412 revealed that CCL5 transcript levels increase significantly at relapse. Taken together, our findings indicate that CCL5 mediates resistance to FLT3-TKIs in FLT3-ITD-mutated AML and could possibly serve as a biomarker to predict drug resistance.
| S-EPMC7138400 | biostudies-literature
Project description:Deregulated mRNA translation has been implicated in disease development and in part is controlled by a eukaryotic initiation complex eIF4F (composed of eIF4E, eIF4G and eIF4A). We demonstrate here that the cap bound fraction from lymphoma cells was enriched with eIF4G and eIF4E indicating that lymphoma cells exist in an activated translational state. Moreover, 77% (110/142) of diffuse large B cell lymphoma tumors expressed eIF4E and this was associated with an inferior event free survival. Over-expression of wild-type eIF4E (eIF4E(WT)) but not cap-mutant eIF4E (eIF4E(cap mutant)) increased the activation of the eIF4F complex. Treatment with the active-site dual mTOR inhibitor CC214-1 reduced the level of the eIF4F complex by decreasing the cap bound fraction of eIF4G and increasing the levels of 4E-BP1. CC214-1 inhibited both the cap dependent and global protein translation. CC214-1 inhibited c-Myc, and cyclin D3 translation by decreasing polysomal fractions from lymphoma cells. Inhibition of eIF4E with shRNA further decreased the CC214-1 induced inhibition of the eIF4F complex, c-Myc, cyclin D3 translation, and colony formation. These studies demonstrate that the eIF4F complex is deregulated in aggressive lymphoma and that dual mTOR therapy has therapeutic potential in these patients.
| S-EPMC4496233 | biostudies-literature