Clinical potential of the mTOR targets S6K1 and S6K2 in breast cancer

Pérez-Tenorio, Gizeh; Karlsson, Elin; Waltersson, Marie Ahnström; Olsson, Birgit; Holmlund, Birgitta; Nordenskjöld, Bo; Fornander, Tommy; Skoog, Lambert; Stål, Olle

doi:10.1007/s10549-010-1058-x

Cited by 61 publications

(69 citation statements)

References 47 publications

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“…[45][46][47] Amplification of eIF4E, S6K1, and cyclin D have been reported in adult cancers, including breast and mantle cell lymphomas but not in pediatric tumors. [48][49][50][51] mTOR-specific mutations in human cancer are extremely rare, with only two reported cases in adult carcinomas. [52] 3.…”

Section: Pi3k/akt/mtor Signaling In Cancermentioning

confidence: 99%

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

et al. 2012

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The phosphatidylinositiol 3-kinase (PI3K), AKT, mammalian target of rapamycin (mTOR) signaling pathway (PI3K/AKT/mTOR) is frequently dysregulated in disorders of cell growth and survival, including a number of pediatric hematologic malignancies. The pathway can be abnormally activated in childhood acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML), as well as in some pediatric lymphomas and lymphoproliferative disorders. Most commonly, this abnormal activation occurs as a consequence of constitutive activation of AKT, providing a compelling rationale to target this pathway in many of these conditions. A variety of agents, beginning with the rapamycin analogue (rapalog) sirolimus, have been used successfully to target this pathway in a number of pediatric hematologic malignancies. Rapalogs demonstrate significant preclinical activity against ALL, which has led to a number of clinical trials. Moreover, rapalogs can synergize with a number of conventional cytotoxic agents and overcome pathways of chemotherapeutic resistance for drugs commonly used in ALL treatment, including methotrexate and corticosteroids. Based on preclinical data, rapalogs are also being studied in AML, CML, and non-Hodgkin's lymphoma. Recently, significant progress has been made using rapalogs to treat pre-malignant lymphoproliferative disorders, including the autoimmune lymphoproliferative syndrome (ALPS); complete remissions in children with otherwise therapy-resistant disease have been seen.Rapalogs only block one component of the pathway (mTORC1), and newer agents are under preclinical and clinical development that can target different and often multiple protein kinases in the PI3K/AKT/mTOR pathway. Most of these agents have been tolerated in early-phase clinical trials. A number of PI3K inhibitors are under investigation. Of note, most of these also target other protein kinases. Newer agents are under development that target both mTORC1 and mTORC2, mTORC1 and PI3K, and the triad of PI3K, mTORC1, and mTORC2. Preclinical data suggest these dual-and multi-kinase inhibitors are more potent than rapalogs against many of the aforementioned hematologic malignancies. Two classes of AKT inhibitors are under development, the alkyl-lysophospholipids (APLs) and small molecule AKT inhibitors. Both classes have agents currently in clinical trials. A number of drugs are in development that target other components of the pathway, including eukaryotic translation initiation factor (eIF) 4E (eIF4E) and phosphoinositide-dependent protein kinase 1 (PDK1). Finally, a number of other key signaling pathways interact with PI3K/AKT/mTOR, including Notch, MNK, Syk, MAPK, and aurora kinase. These alternative pathways are being targeted alone and in combination with PI3K/AKT/mTOR inhibitors with promising preclinical results in pediatric hematologic malignancies. This review provides a comprehensive overview of the abnormalities in the PI3K/AKT/mTOR signaling pathway in pediatric hematologic malignanc...

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Section: Pi3k/akt/mtor Signaling In Cancermentioning

confidence: 99%

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

et al. 2012

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“…miR-145 belongs to a subset of miRs whose expression is promoted by the interaction of microprocessor DICER (83) and zinc finger protein tristetraprolin (TTP) (Figure 4) (84). p70 S6 kinase (p70-S6K), a downstream effector of PI3K signaling (85) and frequently constitutively active in EOC disrupts this interaction by phosphorylating TTP and thus down-regulating expression of miR-145 (79). Metaanalysis in the Oncomine database has indicated that high levels of p70-S6K and low TTP levels are associated with ovarian cancer progression (79).…”

Section: Mir-138mentioning

confidence: 99%

Potential microRNA-related Targets for Therapeutic Intervention with Ovarian Cancer Metastasis

Weidle

Birzele

Kollmorgen

et al. 2018

CGP

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“…Overexpression of the S6K1 gene and deregulated S6K1 signaling have been found in different malignancies, including breast, prostate, thyroid, brain and gastric cancers [13][14][15][16][17][18][19][20][21] that according to multiple studies correlate with poor prognosis of disease [14,[20][21][22]. However, implication of different S6K1 isoforms in carcinogenesis is poorly understood.…”

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confidence: 99%

The Р60-S6K1 isoform of ribosomal protein S6 kinase 1 is a product of alternative mRNA translation

Zaiets¹,

Sivchenko²,

Хоруженко³

et al. 2018

Ukr.Biochem.J.

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Ribosomal protein S6 kinase 1 (S6K1) is a well-known downstream effector of mTORC1 (mechanistic target of rapamycin complex 1) participating primarily in the regulationA number of downstream effects of mTORC1, including protein biosynthesis, cell growth, proliferation and survival [4,5] are mediated via ribosomal protein S6 kinase 1 (S6K1), a well-studied mTORC1 substrate.The S6K1 gene (RPS6KB1) was shown to encode two well-known S6K1 isoforms, p85-S6K1 and p70-S6K1, that differ only by the presence of the Nterminal 23 a.a. extension in p85-S6K1 due to the use of alternative (the first and second ATG) translational start sites [6]. Recently, it has been discovered that the splicing factor SF2/ASF promotes the expression of the oncogenic and the only known S6K1 splice variant termed p31-S6K1 or S6K1-isoform 2 that is truncated from the C-terminus [7]. A mechanism underlying oncogenic properties of p31-S6K1 is unclear but it seems to be kinase-independent, since the kinase domain of the given isoform is severely truncated. e x p e r i m e n T a l w o r K S e x p e r i m e n T a l w o r K S

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Clinical potential of the mTOR targets S6K1 and S6K2 in breast cancer

Cited by 61 publications

References 47 publications

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

Potential microRNA-related Targets for Therapeutic Intervention with Ovarian Cancer Metastasis

The Р60-S6K1 isoform of ribosomal protein S6 kinase 1 is a product of alternative mRNA translation

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