The PI3K/mTOR inhibitor PF-04691502 induces apoptosis and inhibits microenvironmental signaling in CLL and the Eµ-TCL1 mouse model

Blunt, Matthew D.; Carter, Matthew; Larráyoz, Marta; Smith, Lindsay; Aguilar-Hernández, María Montserrat; Cox, Kerry L.; Tipton, Thomas; Reynolds, Mark; Murphy, Sarah; Lemm, Elizabeth; Dias, Samantha; Duncombe, Andrew; Strefford, Jonathan C.; Johnson, Peter; Forconi, Francesco; Stevenson, Freda K.; Packham, Graham; Cragg, Mark S.; Steele, Andrew J.

doi:10.1182/blood-2014-11-610329

Cited by 37 publications

(34 citation statements)

References 51 publications

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“…Attempts have been recently made to apply mTOR inhibitors in treatment of leukemia, including CLL [41, 42, 43]. Along the rationale presented above the patients with high level of RDW are expected to have an increased persistent level of IGF-1/mTOR signaling.…”

Section: Discussionmentioning

confidence: 99%

Assessment of red blood cell distribution width as a prognostic marker in chronic lymphocytic leukemia

et al. 2016

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Red blood cell distribution width (RDW) is a quantitative measure of the variability in size of circulating erythrocytes. It was recently reported that RDW is a prognostic factor for infection diseases, cardiovascular and pulmonary diseases, as well as some neoplasms. Moreover, RDW is remarkably strong predictor of longevity, including all causes of death, for adults aged 45 years and older. To explain this occurrence it was proposed that persistent IGFs/mTOR signaling is one of the factors that play a role in affecting the RDW and mortality.The above observations induced us to analyze the prognostic role of RDW in chronic lymphocytic leukemia (CLL) being the most frequent type of adult leukemia in Western countries. The obtained results have shown that RDW may be considered as a potential CLL prognostic marker. Elevated RDW level at the moment of diagnosis was associated with advanced disease and presence of other poor prognostic factors. It is also connected with overall survival indicating shorter time in patients with elevated RDW. It is possible that the presently observed correlation between mortality and RDW of the CLL patients is affected by their metabolic (IGF-1/mTOR driven)- rather than chronological- aging. The patients with high level of RDW are expected to have an increased persistent level of IGF-1/mTOR signaling. Within the framework of personalized therapy, these CLL patients therefore would be expected to be more sensitive to the treatment with mTOR inhibitors.

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Section: Discussionmentioning

confidence: 99%

Assessment of red blood cell distribution width as a prognostic marker in chronic lymphocytic leukemia

et al. 2016

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“…[13][14][15] The PI3K-related protein kinase (PIKK) family includes mammalian target of rapamycin kinase (TORK), ataxia telangiectasia mutated (ATM), ataxia telangiectasia and Rad3 related (ATR), and DNA-dependent protein kinase (DNA-PK). TORK is the main downstream kinase of the PI3K/AKT pathway and exists in 2 protein complexes: mTORC1 and mTORC2.…”

Section: Introductionmentioning

confidence: 99%

Dual TORK/DNA-PK inhibition blocks critical signaling pathways in chronic lymphocytic leukemia

Thijssen

Burg

Garrick³

et al. 2016

Blood

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“…In addition, emerging evidence has revealed that the inhibition of MTOR signaling mediated the induction of apoptosis under various conditions; for instance, thymosin alpha 1 executed this effect in breast cancer [10]. It was reported that the inhibition of MTOR by pharmaceutical treatment, such as PF-04691502 [11], NVP-BEZ235 [12], and AZD8055 [13], can promote apoptosis, although these inhibitors affected MTOR activity through the indirect regulation of MTOR instead of the mediation of PI3K signaling. Indeed, some direct MTOR inhibitors have also been reported to induce apoptosis, for example, pp242 [14], temsirolimus [15], and everolimus [16].…”

Section: Introductionmentioning

confidence: 99%

Impact on Autophagy and Ultraviolet B Induced Responses of Treatment with the MTOR Inhibitors Rapamycin, Everolimus, Torin 1, and pp242 in Human Keratinocytes

et al. 2017

Oxidative Medicine and Cellular Longevity

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The mechanistic target of Rapamycin (MTOR) protein is a crucial signaling regulator in mammalian cells that is extensively involved in cellular biology. The function of MTOR signaling in keratinocytes remains unclear. In this study, we detected the MTOR signaling and autophagy response in the human keratinocyte cell line HaCaT and human epidermal keratinocytes treated with MTOR inhibitors. Moreover, we detected the impact of MTOR inhibitors on keratinocytes exposed to the common carcinogenic stressors ultraviolet B (UVB) and UVA radiation. As a result, keratinocytes were sensitive to the MTOR inhibitors Rapamycin, everolimus, Torin 1, and pp242, but the regulation of MTOR downstream signaling was distinct. Next, autophagy induction only was observed in HaCaT cells treated with Rapamycin. Furthermore, we found that MTOR signaling was insensitive to UVB but sensitive to UVA radiation. UVB treatment also had no impact on the inhibition of MTOR signaling by MTOR inhibitors. Finally, MTOR inhibition by Rapamycin, everolimus, or pp242 did not affect the series of biological events in keratinocytes exposed to UVB, including the downregulation of BiP and PERK, activation of Histone H2A and JNK, and cleavage of caspase-3 and PARP. Our study demonstrated that MTOR inhibition in keratinocytes cannot always induce autophagy, and the MTOR pathway does not play a central role in the UVB triggered cellular response.

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The PI3K/mTOR inhibitor PF-04691502 induces apoptosis and inhibits microenvironmental signaling in CLL and the Eµ-TCL1 mouse model

Abstract: Key Points PF-04691502 induces potent apoptosis in CLL cells and suppresses prosurvival anti–immunoglobulin M signaling and CXCL12-induced migration. PF-04691502 displays powerful antitumor effects in vivo in the Eμ-TCL1 mouse model.

Cited by 37 publications

References 51 publications

Assessment of red blood cell distribution width as a prognostic marker in chronic lymphocytic leukemia

Assessment of red blood cell distribution width as a prognostic marker in chronic lymphocytic leukemia

Dual TORK/DNA-PK inhibition blocks critical signaling pathways in chronic lymphocytic leukemia

Impact on Autophagy and Ultraviolet B Induced Responses of Treatment with the MTOR Inhibitors Rapamycin, Everolimus, Torin 1, and pp242 in Human Keratinocytes

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