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Dual modulation of ...
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Elgendy, MohamedEuropean Inst Oncol IEO, Dept Expt Oncol, Milan, Italy.;Univ Vienna, Max F Perutz Labs, Dept Microbiol & Immunobiol, Dr Bohr Gasse 9, A-1030 Vienna, Austria.
(författare)
Dual modulation of MCL-1 and mTOR determines the response to sunitinib
- Artikel/kapitelEngelska2017
Förlag, utgivningsår, omfång ...
Nummerbeteckningar
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LIBRIS-ID:oai:DiVA.org:uu-316415
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-316415URI
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https://doi.org/10.1172/JCI84386DOI
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Språk:engelska
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Sammanfattning på:engelska
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Ämneskategori:ref swepub-contenttype
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Ämneskategori:art swepub-publicationtype
Anmärkningar
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Most patients who initially respond to treatment with the multi-tyrosine kinase inhibitor sunitinib eventually relapse. Therefore, developing a deeper understanding of the contribution of sunitinib's numerous targets to the clinical response or to resistance is crucial. Here, we have shown that cancer cells respond to clinically relevant doses of sunitinib by enhancing the stability of the antiapoptotic protein MCL-1 and inducing mTORC1 signaling, thus evoking little cytotoxicity. Inhibition of MCL-1 or mTORC1 signaling sensitized cells to clinically relevant doses of sunitinib in vitro and was synergistic with sunitinib in impairing tumor growth in vivo, indicating that these responses are triggered as prosurvival mechanisms that enable cells to tolerate the cytotoxic effects of sunitinib. Furthermore, higher doses of sunitinib were cytotoxic, triggered a decline in MCL-1 levels, and inhibited mTORC1 signaling. Mechanistically, we determined that sunitinib modulates MCL-1 stability by affecting its proteasomal degradation. Dual modulation of MCL-1 stability at different dose ranges of sunitinib was due to differential effects on ERK and GSK3 beta activity, and the latter also accounted for dual modulation of mTORC1 activity. Finally, comparison of patient samples prior to and following sunitinib treatment suggested that increases in MCL-1 levels and mTORC1 activity correlate with resistance to sunitinib in patients.
Ämnesord och genrebeteckningar
Biuppslag (personer, institutioner, konferenser, titlar ...)
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Abdel-Aziz, Amal KamalEuropean Inst Oncol IEO, Dept Expt Oncol, Milan, Italy.;Ain Shams Univ, Dept Pharmacol & Toxicol, Fac Pharm, Cairo, Egypt.
(författare)
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Renne, Salvatore LorenzoFdn IRCCS Ist Nazl Tumori, Dept Pathol & Lab Med, Milan, Italy.
(författare)
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Bornaghi, VivianaEuropean Inst Oncol IEO, Dept Expt Oncol, Milan, Italy.
(författare)
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Procopio, GiuseppeFdn IRCCS Ist Nazl Tumori, Genitourinary Oncol Unit, Milan, Italy.
(författare)
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Colecchia, MaurizioFdn IRCCS Ist Nazl Tumori, Dept Pathol & Lab Med, Milan, Italy.
(författare)
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Kanesvaran, RavindranNatl Canc Ctr Singapore, Div Med Oncol, Singapore, Singapore.;Duke NUS Med Sch, Singapore, Singapore.
(författare)
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Toh, Chee KeongNatl Canc Ctr Singapore, Div Med Oncol, Singapore, Singapore.
(författare)
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Bossi, DanielaEuropean Inst Oncol IEO, Dept Expt Oncol, Milan, Italy.
(författare)
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Pallavicini, IsabellaEuropean Inst Oncol IEO, Dept Expt Oncol, Milan, Italy.
(författare)
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Luis Perez-Gracia, JoseUniv Navarra Clin, Dept Oncol, Pamplona, Spain.
(författare)
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Dolores Lozano, MariaUniv Navarra Clin, Dept Pathol, Pamplona, Spain.
(författare)
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Giandomenico, ValeriaUppsala universitet,Endokrin tumörbiologi(Swepub:uu)valegian
(författare)
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Mercurio, CiroIFOM, Unit Expt Therapies, Milan, Italy.
(författare)
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Lanfrancone, LuisaEuropean Inst Oncol IEO, Dept Expt Oncol, Milan, Italy.
(författare)
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Fazio, NicolaEuropean Inst Oncol, Unit Gastrointestinal Med Oncol & Neuroendocrine, Milan, Italy.
(författare)
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Nole, FrancoIEO, Dept Clin Oncol, Milan, Italy.
(författare)
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Teh, Bin TeanDuke NUS Med Sch, Singapore, Singapore.;Natl Canc Ctr Singapore, Div Med Sci, Singapore, Singapore.;Canc Sci Inst, Singapore, Singapore.;Inst Mol & Cell Biol, Singapore, Singapore.
(författare)
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Renne, GiuseppeDept Pathol IEO, Milan, Italy.
(författare)
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Minucci, SaverioEuropean Inst Oncol IEO, Dept Expt Oncol, Milan, Italy.;Univ Milan, Dept Biosci, Milan, Italy.;IEO, Drug Dev Program, Milan, Italy.
(författare)
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European Inst Oncol IEO, Dept Expt Oncol, Milan, Italy.;Univ Vienna, Max F Perutz Labs, Dept Microbiol & Immunobiol, Dr Bohr Gasse 9, A-1030 Vienna, Austria.European Inst Oncol IEO, Dept Expt Oncol, Milan, Italy.;Ain Shams Univ, Dept Pharmacol & Toxicol, Fac Pharm, Cairo, Egypt.
(creator_code:org_t)
Sammanhörande titlar
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Ingår i:Journal of Clinical Investigation127:1, s. 153-1680021-97381558-8238
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Till lärosätets databas
- Av författaren/redakt...
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Elgendy, Mohamed
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Abdel-Aziz, Amal ...
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Renne, Salvatore ...
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Bornaghi, Vivian ...
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Procopio, Giusep ...
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Colecchia, Mauri ...
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visa fler...
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Kanesvaran, Ravi ...
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Toh, Chee Keong
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Bossi, Daniela
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Pallavicini, Isa ...
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Luis Perez-Graci ...
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Dolores Lozano, ...
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Giandomenico, Va ...
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Mercurio, Ciro
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Lanfrancone, Lui ...
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Fazio, Nicola
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Nole, Franco
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Teh, Bin Tean
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Renne, Giuseppe
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Minucci, Saverio
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visa färre...
- Om ämnet
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Klinisk medicin
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och Cancer och onkol ...
- Artiklar i publikationen
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Journal of Clini ...
- Av lärosätet
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Uppsala universitet