FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2620599910> ?p ?o ?g. }

• W2620599910 abstract "Abstract Chronic lymphocytic leukaemia (CLL), often diagnosed in the elderly, is incurable with current therapeutic regimes. Recent studies demonstrate that the microenvironment within CLL patient lymphoid organs protects leukaemic cells from chemotherapy induced apoptosis. This highlights the need for novel therapies that can overcome such cytoprotective signals. Serine/threonine protein kinase mammalian target for rapamycin (mTOR) is a key regulator of cell survival and proliferation and is commonly deregulated in cancer. mTOR is active in two complexes mTORC1 and mTORC2. We demonstrate that mTORC1 and mTORC2 substrates, including S6 (pS6S235/236) and Akt (pAktS473) respectively, are active although differentially regulated, in CLL cells from distinct prognostic subsets ex vivo, which suggests that mTOR may represent a valid therapeutic target for CLL. Initial studies with everolimus, an analogue of rapamycin, showed only limited antitumor activity in recurrent/refractory CLL patients, possibly because mTORC1 inhibition releases the brake that normally active mTORC1 has on mTORC2, thus enabling mTORC2 mediated signalling. To test the impact of inhibiting both mTORC1 and mTORC2 on cell proliferation and survival, we treated primary CLL cells and an aggressive CLL mouse model with the novel ATP-competitive mTOR inhibitor AZD8055 in vitro and in vivo. CLL proliferation and mTORC1/2 activity were significantly reduced upon addition of AZD8055 to NTL-CD154/IL4 co-cultures, which mimic pro-proliferative conditions present in the microenvironment of lymphoid organs. However, in the same conditions use of AZD8055 did not induce apoptosis at clinically-achievable drug concentrations (<150 nM), likely due to ineffective inhibition of Mcl-1 upregulation mediated by the NTL-CD154/IL4 co-cultures. In contrast, B cell receptor (BCR)-mediated survival was inhibited by AZD8055 treatment, inducing significant levels of apoptosis, concomitant with a decreased Mcl-1 expression. These findings suggest that the BCR and CD154/IL4 mediated pathways regulate Mcl-1 expression by distinct mechanisms. In vivo studies using the PKCa-KR-induced CLL mouse model revealed that AZD8055 treatment efficiently reduced tumour burden in the organs (spleen and bone marrow) and blood of mice with established CLL. This was reflected by in vitro studies showing that use of AZD8055 increased apoptosis and reduced proliferation in mouse CLL cells. Overall these data indicate that AZD8055 inhibits CLL proliferation, in vitro and in vivo, and disrupts BCR mediated survival, by downregulating Mcl-1 protein levels. Therefore dual mTOR inhibitors through reduction of tumour burden, show promise as a future therapy for CLL. Disclosures No relevant conflicts of interest to declare." @default.
• W2620599910 created "2017-06-09" @default.
• W2620599910 creator A5021978395 @default.
• W2620599910 creator A5045823910 @default.
• W2620599910 creator A5051652459 @default.
• W2620599910 creator A5053321245 @default.
• W2620599910 creator A5070551431 @default.
• W2620599910 creator A5084172041 @default.
• W2620599910 date "2015-12-03" @default.
• W2620599910 modified "2023-09-29" @default.
• W2620599910 title "The ATP-Competitive mTOR Inhibitor AZD8055 Reduces Cell Proliferation and Tumour Load in Chronic Lymphocytic Leukaemia" @default.
• W2620599910 doi "https://doi.org/10.1182/blood.v126.23.5287.5287" @default.
• W2620599910 hasPublicationYear "2015" @default.
• W2620599910 type Work @default.
• W2620599910 sameAs 2620599910 @default.
• W2620599910 citedByCount "0" @default.
• W2620599910 crossrefType "journal-article" @default.
• W2620599910 hasAuthorship W2620599910A5021978395 @default.
• W2620599910 hasAuthorship W2620599910A5045823910 @default.
• W2620599910 hasAuthorship W2620599910A5051652459 @default.
• W2620599910 hasAuthorship W2620599910A5053321245 @default.
• W2620599910 hasAuthorship W2620599910A5070551431 @default.
• W2620599910 hasAuthorship W2620599910A5084172041 @default.
• W2620599910 hasConcept C107846503 @default.
• W2620599910 hasConcept C190283241 @default.
• W2620599910 hasConcept C2779699572 @default.
• W2620599910 hasConcept C502942594 @default.
• W2620599910 hasConcept C54355233 @default.
• W2620599910 hasConcept C55493867 @default.
• W2620599910 hasConcept C62112901 @default.
• W2620599910 hasConcept C75217442 @default.
• W2620599910 hasConcept C86554907 @default.
• W2620599910 hasConcept C86803240 @default.
• W2620599910 hasConcept C98490376 @default.
• W2620599910 hasConceptScore W2620599910C107846503 @default.
• W2620599910 hasConceptScore W2620599910C190283241 @default.
• W2620599910 hasConceptScore W2620599910C2779699572 @default.
• W2620599910 hasConceptScore W2620599910C502942594 @default.
• W2620599910 hasConceptScore W2620599910C54355233 @default.
• W2620599910 hasConceptScore W2620599910C55493867 @default.
• W2620599910 hasConceptScore W2620599910C62112901 @default.
• W2620599910 hasConceptScore W2620599910C75217442 @default.
• W2620599910 hasConceptScore W2620599910C86554907 @default.
• W2620599910 hasConceptScore W2620599910C86803240 @default.
• W2620599910 hasConceptScore W2620599910C98490376 @default.
• W2620599910 hasLocation W26205999101 @default.
• W2620599910 hasOpenAccess W2620599910 @default.
• W2620599910 hasPrimaryLocation W26205999101 @default.
• W2620599910 hasRelatedWork W1024089907 @default.
• W2620599910 hasRelatedWork W127788025 @default.
• W2620599910 hasRelatedWork W1977978614 @default.
• W2620599910 hasRelatedWork W2026096732 @default.
• W2620599910 hasRelatedWork W2029098356 @default.
• W2620599910 hasRelatedWork W2050072022 @default.
• W2620599910 hasRelatedWork W2072583138 @default.
• W2620599910 hasRelatedWork W2084839831 @default.
• W2620599910 hasRelatedWork W2097858421 @default.
• W2620599910 hasRelatedWork W2113365503 @default.
• W2620599910 hasRelatedWork W2118502374 @default.
• W2620599910 hasRelatedWork W2255127096 @default.
• W2620599910 hasRelatedWork W2259314598 @default.
• W2620599910 hasRelatedWork W2555700808 @default.
• W2620599910 hasRelatedWork W2592973432 @default.
• W2620599910 hasRelatedWork W2741063213 @default.
• W2620599910 hasRelatedWork W2916037227 @default.
• W2620599910 hasRelatedWork W2973135157 @default.
• W2620599910 hasRelatedWork W3108746969 @default.
• W2620599910 hasRelatedWork W2030954686 @default.
• W2620599910 isParatext "false" @default.
• W2620599910 isRetracted "false" @default.
• W2620599910 magId "2620599910" @default.
• W2620599910 workType "article" @default.