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Sökning: onr:"swepub:oai:DiVA.org:uu-316415" > Dual modulation of ...

Dual modulation of MCL-1 and mTOR determines the response to sunitinib

Elgendy, Mohamed (författare)
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.
Abdel-Aziz, Amal Kamal (författare)
European Inst Oncol IEO, Dept Expt Oncol, Milan, Italy.;Ain Shams Univ, Dept Pharmacol & Toxicol, Fac Pharm, Cairo, Egypt.
Renne, Salvatore Lorenzo (författare)
Fdn IRCCS Ist Nazl Tumori, Dept Pathol & Lab Med, Milan, Italy.
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Bornaghi, Viviana (författare)
European Inst Oncol IEO, Dept Expt Oncol, Milan, Italy.
Procopio, Giuseppe (författare)
Fdn IRCCS Ist Nazl Tumori, Genitourinary Oncol Unit, Milan, Italy.
Colecchia, Maurizio (författare)
Fdn IRCCS Ist Nazl Tumori, Dept Pathol & Lab Med, Milan, Italy.
Kanesvaran, Ravindran (författare)
Natl Canc Ctr Singapore, Div Med Oncol, Singapore, Singapore.;Duke NUS Med Sch, Singapore, Singapore.
Toh, Chee Keong (författare)
Natl Canc Ctr Singapore, Div Med Oncol, Singapore, Singapore.
Bossi, Daniela (författare)
European Inst Oncol IEO, Dept Expt Oncol, Milan, Italy.
Pallavicini, Isabella (författare)
European Inst Oncol IEO, Dept Expt Oncol, Milan, Italy.
Luis Perez-Gracia, Jose (författare)
Univ Navarra Clin, Dept Oncol, Pamplona, Spain.
Dolores Lozano, Maria (författare)
Univ Navarra Clin, Dept Pathol, Pamplona, Spain.
Giandomenico, Valeria (författare)
Uppsala universitet,Endokrin tumörbiologi
Mercurio, Ciro (författare)
IFOM, Unit Expt Therapies, Milan, Italy.
Lanfrancone, Luisa (författare)
European Inst Oncol IEO, Dept Expt Oncol, Milan, Italy.
Fazio, Nicola (författare)
European Inst Oncol, Unit Gastrointestinal Med Oncol & Neuroendocrine, Milan, Italy.
Nole, Franco (författare)
IEO, Dept Clin Oncol, Milan, Italy.
Teh, Bin Tean (författare)
Duke 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.
Renne, Giuseppe (författare)
Dept Pathol IEO, Milan, Italy.
Minucci, Saverio (författare)
European Inst Oncol IEO, Dept Expt Oncol, Milan, Italy.;Univ Milan, Dept Biosci, Milan, Italy.;IEO, Drug Dev Program, Milan, Italy.
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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)
2017
2017
Engelska.
Ingår i: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 127:1, s. 153-168
Relaterad länk:
https://urn.kb.se/re...
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https://doi.org/10.1...
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  • Tidskriftsartikel (refereegranskat)
Abstract Ämnesord
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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

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

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