mTOR inhibitor therapy as a disease modifying therapy for tuberous sclerosis complex

Franz, David Neal; Krueger, Darcy A.

doi:10.1002/ajmg.c.31655

Cited by 44 publications

(36 citation statements)

References 40 publications

(64 reference statements)

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“…Notably, hyperactivated mTORC1, caused by loss-of-function mutations in the TSC1 or TSC2 gene, is considered to be the main reason of tuberous sclerosis complex (TSC), an autosomal dominant disease characterized by formation of benign tumors in multiple organs [6]. Currently, the mTORC1 inhibitors, rapamycin as well as its analogues have been approved for the treatment of several types of human cancer, such as renal cell carcinoma, mantle cell lymphoma, and some TSCrelated tumors, including lymphangioleiomyomatosis, angiomyolipomas, and subependymal giant cell astrocytomas [6,[16][17][18]. Numerous studies indicate that mTORC1 signaling pathway is regulated by miRNAs [10].…”

Section: Discussionmentioning

confidence: 99%

miR-125b-5p/STAT3 Pathway Regulated by mTORC1 Plays a Critical Role in Promoting Cell Proliferation and Tumor Growth

Zhang¹,

Wan²,

Tang³

et al. 2020

J. Cancer

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Aberrant activation of the mammalian target of rapamycin complex 1 (mTORC1) plays a critical role in tumorigenesis. However, the precise underlying mechanism is still not fully understood. Although accumulating evidence suggests that mTORC1 signaling is regulated by microRNAs (miRNAs), whether miRNAs are involved in the tumorigenesis mediated by mTORC1 dysregulation remains largely unclear. In our study, the comparison between tuberous sclerosis complex 1 (Tsc1) -/-or Tsc2-/-mouse embryonic fibroblasts (MEFs) and the control cells revealed the involvement of microRNA-125b-5p (miR-125b-5p) in the tumorigenesis driven by mTORC1 activation. Our study also showed that loss of TSC1 or TSC2 led to significant downregulation of miR-125b-5p and upregulation of signal transducer and activator of transcription 3 (STAT3) via mTORC1 activation. Overexpression of miR-125b-5p inhibited the proliferation of the cells with hyperactivated mTORC1 both in vitro and in vivo. Furthermore, we demonstrated that STAT3 is a direct target of miR-125b-5p. Depletion of STAT3 mimicked the effect of ectopic expression of miR-125b-5p, and reintroduction of STAT3 rescued the compromised cell proliferation driven by miR-125b-5p overexpression in Tsc1-/-or Tsc2-/-MEFs. We conclude that the miR-125b-5p/STAT3 pathway plays a crucial role in hyperactivated mTORC1-mediated tumorigenesis and miR-125b-5p is a potential therapeutic target.

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Section: Discussionmentioning

confidence: 99%

miR-125b-5p/STAT3 Pathway Regulated by mTORC1 Plays a Critical Role in Promoting Cell Proliferation and Tumor Growth

Zhang¹,

Wan²,

Tang³

et al. 2020

J. Cancer

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“…The incidence of TSC is 1 in 6,000-10,000 live births, and it affects nearly 2 million individuals worldwide (Curatolo et al, 2008;Peron and Northrup, 2018). TSC is the result of mutations in either the TSC1 (OMIM #605284) or TSC2 (OMIM #191092) gene, triggering the hyperactivation of the mechanistic target of rapamycin (mTOR) signaling pathway, and subsequent cell proliferation deregulation (Cheadle et al, 2000;Crino et al, 2006;Henske et al, 2016;Franz and Krueger, 2018).…”

Section: Introductionmentioning

confidence: 99%

Genotype and Phenotype Analysis of Chinese Children With Tuberous Sclerosis Complex: A Pediatric Cohort Study

Ding

Zhou

et al. 2020

Front. Genet.

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Tuberous sclerosis complex (TSC) is a genetic condition characterized by the occurrence of hamartomatous wounds stemming from the dysfunction of the mammalian target of rapamycin (mTOR) pathway. We investigated the clinical phenotypes and genetic variants in 243 unrelated probands and their families in China. Exome sequencing, targeted sequencing or multiplex ligation-dependent probe amplification (MLPA) was performed in 174 children with TSC, among whom 31 (17.82%) patients/families were identified as having pathogenic or likely pathogenic variants in the TSC1 gene, 120 (68.97%) as having pathogenic or likely pathogenic variants in the TSC2 gene and 23 (13.21%) as having no pathogenic or likely pathogenic variants identified (NMI). In the 31 patients with pathogenic or likely pathogenic TSC1 variants, 10 novel variants were detected among 26 different variants. In all 120 patients with TSC2 variants, 39 novel variants were found among a total of 107 different variants. We compared the phenotypes of the individuals with TSC1 pathogenic variants, TSC2 pathogenic variants and NMI. Patients with TSC2 variants were first diagnosed at a younger age (p = 0.003) and had more retinal hamartomas (p = 0.003) and facial angiofibromas (p = 0.027) (age ≥ 3 years) than individuals with TSC1 variants. Compared with individuals with TSC1/TSC2 pathogenic variants, NMI individuals had fewer cortical tubers (p = 0.003). Compared with individuals with TSC1 pathogenic variants, NMI patients had more retinal hamartomas (p = 0.035), and compared with individuals with TSC2 pathogenic variants, they had less epilepsy (p = 0.003) and fewer subependymal nodules (SENs) (p = 0.004).

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“…Given that hyperactivated mTORC1 is the main etiology of the TSC tumors, the inhibitor of mTORC1, rapamycin, and its analogs (rapalogs) have been considered as ideal drugs for the treatment of TSC. 3,41 However, some disadvantages, such as incomplete inhibition of mTORC1 and the ill-defined duration of therapy, limited the clinical application of rapamycin and its analogs. 9,42,43 Increasing treatment efficacy and reducing side effects by rational combination of different drugs is a widely used strategy for cancer treatment.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of 6‐phosphofructo‐2‐kinase (PFKFB3) by hyperactivated mammalian target of rapamycin complex 1 is critical for tumor growth in tuberous sclerosis complex

Wang

Tang

et al. 2020

IUBMB Life

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Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterized by the benign tumor formation in multiple organs. The main etiology of TSC is the loss‐of‐function mutation of TSC1 or TSC2 gene, which leads to aberrant activation of mammalian target of rapamycin complex 1 (mTORC1). In this research, we found a significant increase of 6‐phosphofructo‐2‐kinase/fructose‐2,6‐biphosphatase 3 (PFKFB3) expression in Tsc1−/− and Tsc2−/− mouse embryonic fibroblasts (MEFs) compared with the control cells. Inhibition of mTORC1 led to a dramatic decrease of PFKFB3 expression, indicating PFKFB3 regulation by mTORC1. Moreover, suppression of mTORC1 inhibited the expression of PFKFB3 in rat uterine leiomyoma‐derived Tsc2‐null ELT3 cells and human tumor cells. Furthermore, we identified hypoxia‐inducible factor 1α (HIF‐1α) as a mediator transmitting the signal from mTORC1 to PFKFB3. Depletion of PFKFB3 inhibited proliferation and tumorigenicity of Tsc1‐ or Tsc2‐deficient cells. In addition, combination of rapamycin with PFK15, a PFKFB3 inhibitor, exerts a stronger inhibitory effect on cell proliferation of Tsc1‐ or Tsc2‐null MEFs than treatment with single drug. We conclude that loss of TSC1 or TSC2 led to upregulated expression of PFKFB3 through activation of mTORC1/HIF‐1α signaling pathway and co‐administration of rapamycin and PFK15 may be a promising strategy for the treatment of TSC tumors as well as other hyperactivated mTORC1‐related tumors.

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mTOR inhibitor therapy as a disease modifying therapy for tuberous sclerosis complex

Cited by 44 publications

References 40 publications

miR-125b-5p/STAT3 Pathway Regulated by mTORC1 Plays a Critical Role in Promoting Cell Proliferation and Tumor Growth

miR-125b-5p/STAT3 Pathway Regulated by mTORC1 Plays a Critical Role in Promoting Cell Proliferation and Tumor Growth

Genotype and Phenotype Analysis of Chinese Children With Tuberous Sclerosis Complex: A Pediatric Cohort Study

Upregulation of 6‐phosphofructo‐2‐kinase (PFKFB3) by hyperactivated mammalian target of rapamycin complex 1 is critical for tumor growth in tuberous sclerosis complex

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