The protein arginine methyltransferase PRMT5 confers therapeutic resistance to mTOR inhibition in glioblastoma

Holmes, Brent; Benavides-Serrato, Angelica; Saunders, Jacquelyn T; Landon, Kenna A.; Schreck, Adam J; Nishimura, Robert N.; Gera, Joseph

doi:10.1007/s11060-019-03274-0

Cited by 36 publications

(40 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent efforts to gain insights into such resistance mechanisms underscore the ability of cancer cells to restore key metabolic processes that support their growth and proliferation. For example, proteomics and genomics studies that analyzed changes that occur after treatment with mTOR inhibitors revealed bypass mechanisms related to protein synthesis in Ewing sarcoma cells [333] and glioblastoma [334]. Using metabolomics studies, another resistance mechanism occurring due to PI3K/mTOR inhibition is via upregulation of the purine salvage pathway in small cell lung carcinoma [335].…”

Section: Resistance Mechanisms and Other Therapeutic Opportunitiesmentioning

confidence: 99%

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Magaway

Kim

Jacinto

2019

Cells

165

128

View full text Add to dashboard Cite

Cancer cells support their growth and proliferation by reprogramming their metabolism in order to gain access to nutrients. Despite the heterogeneity in genetic mutations that lead to tumorigenesis, a common alteration in tumors occurs in pathways that upregulate nutrient acquisition. A central signaling pathway that controls metabolic processes is the mTOR pathway. The elucidation of the regulation and functions of mTOR can be traced to the discovery of the natural compound, rapamycin. Studies using rapamycin have unraveled the role of mTOR in the control of cell growth and metabolism. By sensing the intracellular nutrient status, mTOR orchestrates metabolic reprogramming by controlling nutrient uptake and flux through various metabolic pathways. The central role of mTOR in metabolic rewiring makes it a promising target for cancer therapy. Numerous clinical trials are ongoing to evaluate the efficacy of mTOR inhibition for cancer treatment. Rapamycin analogs have been approved to treat specific types of cancer. Since rapamycin does not fully inhibit mTOR activity, new compounds have been engineered to inhibit the catalytic activity of mTOR to more potently block its functions. Despite highly promising pre-clinical studies, early clinical trial results of these second generation mTOR inhibitors revealed increased toxicity and modest antitumor activity. The plasticity of metabolic processes and seemingly enormous capacity of malignant cells to salvage nutrients through various mechanisms make cancer therapy extremely challenging. Therefore, identifying metabolic vulnerabilities in different types of tumors would present opportunities for rational therapeutic strategies. Understanding how the different sources of nutrients are metabolized not just by the growing tumor but also by other cells from the microenvironment, in particular, immune cells, will also facilitate the design of more sophisticated and effective therapeutic regimen. In this review, we discuss the functions of mTOR in cancer metabolism that have been illuminated from pre-clinical studies. We then review key findings from clinical trials that target mTOR and the lessons we have learned from both pre-clinical and clinical studies that could provide insights on innovative therapeutic strategies, including immunotherapy to target mTOR signaling and the metabolic network in cancer.

show abstract

Section: Resistance Mechanisms and Other Therapeutic Opportunitiesmentioning

confidence: 99%

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Magaway

Kim

Jacinto

2019

Cells

165

128

View full text Add to dashboard Cite

show abstract

“…Cell proliferation was determined via Cell Titer-Glo ® luminescent cell assays (Promega) and cell-cycle analysis was done by propidium iodide staining of cells and flow cytometry as previously described [61]. Cells were stained using a FITC-conjugated annexin V (Annexin V-FITC Early Apoptosis Detection kit, Cell Signaling Technology) to monitor apoptosis.…”

Section: Cell Proliferation Cell-cycle Distribution and Tunel Assaysmentioning

confidence: 99%

Repurposing Potential of Riluzole as an ITAF Inhibitor in mTOR Therapy Resistant Glioblastoma

Benavides-Serrato

Saunders

Holmes

et al. 2020

IJMS

Self Cite

View full text Add to dashboard Cite

Internal ribosome entry site (IRES)-mediated protein synthesis has been demonstrated to play an important role in resistance to mechanistic target of rapamycin (mTOR) targeted therapies. Previously, we have demonstrated that the IRES trans-acting factor (ITAF), hnRNP A1 is required to promote IRES activity and small molecule inhibitors which bind specifically to this ITAF and curtail IRES activity, leading to mTOR inhibitor sensitivity. Here we report the identification of riluzole (Rilutek®), an FDA-approved drug for amyotrophic lateral sclerosis (ALS), via an in silico docking analysis of FDA-approved compounds, as an inhibitor of hnRNP A1. In a riluzole-bead coupled binding assay and in surface plasmon resonance imaging analyses, riluzole was found to directly bind to hnRNP A1 and inhibited IRES activity via effects on ITAF/RNA-binding. Riluzole also demonstrated synergistic anti-glioblastoma (GBM) affects with mTOR inhibitors in vitro and in GBM xenografts in mice. These data suggest that repurposing riluzole, used in conjunction with mTOR inhibitors, may serve as an effective therapeutic option in glioblastoma.

show abstract

“…Somatic PTEN mutations in GB patients also develop resistance to immune checkpoint inhibitors (Nivolumab: an anti-PD-1 inhibitor) by changing immunosuppressive environments ( 183 ). Similarly, mTOR inhibitors activate protein arginine methyltransferase, which provides resistance in mTOR inhibitor therapy in GB ( 184 ). Thus, a complete understanding of the genetic status of PTEN in GB, including deletion, inactivating mutation, and post-translational alteration can enhance effective treatments for patients.…”

Section: Development Of Oncogenic Addiction To Pten Loss and Drug Resmentioning

confidence: 99%

Role of Ubiquitination in PTEN Cellular Homeostasis and Its Implications in GB Drug Resistance

et al. 2020

View full text Add to dashboard Cite

Glioblastoma (GB) is the most common and aggressive brain malignancy, characterized by heterogeneity and drug resistance. PTEN, a crucial tumor suppressor, exhibits phosphatase-dependent (PI3K-AKT-mTOR pathway)/independent (nucleus stability) activities to maintain the homeostatic regulation of numerous physiological processes. Premature and absolute loss of PTEN activity usually tends to cellular senescence. However, monoallelic loss of PTEN is frequently observed at tumor inception, and absolute loss of PTEN activity also occurs at the late stage of gliomagenesis. Consequently, aberrant PTEN homeostasis, mainly regulated at the post-translational level, renders cells susceptible to tumorigenesis and drug resistance. Ubiquitination-mediated degradation or deregulated intracellular localization of PTEN hijacks cell growth rheostat control for neoplastic remodeling. Functional inactivation of PTEN mediated by the overexpression of ubiquitin ligases (E3s) renders GB cells adaptive to PTEN loss, which confers resistance to EGFR tyrosine kinase inhibitors and immunotherapies. In this review, we discuss how glioma cells develop oncogenic addiction to the E3s-PTEN axis, promoting their growth and proliferation. Antitumor strategies involving PTEN-targeting E3 ligase inhibitors can restore the tumor-suppressive environment. E3 inhibitors collectively reactivate PTEN and may represent next-generation treatment against deadly malignancies such as GB.

show abstract

The protein arginine methyltransferase PRMT5 confers therapeutic resistance to mTOR inhibition in glioblastoma

Cited by 36 publications

References 39 publications

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Targeting mTOR and Metabolism in Cancer: Lessons and Innovations

Repurposing Potential of Riluzole as an ITAF Inhibitor in mTOR Therapy Resistant Glioblastoma

Role of Ubiquitination in PTEN Cellular Homeostasis and Its Implications in GB Drug Resistance

Contact Info

Product

Resources

About