title: Dual modulation of MCL-1 and mTOR determines the response to sunitinib.
abstract: 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 GSK3β 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.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Elgendy
authors.forename: Amal Kamal
authors.initials: AK
authors.lastname: Abdel-Aziz
authors.forename: Salvatore Lorenzo
authors.initials: SL
authors.lastname: Renne
authors.forename: Viviana
authors.initials: V
authors.lastname: Bornaghi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Procopio
authors.forename: Maurizio
authors.initials: M
authors.lastname: Colecchia
authors.forename: Ravindran
authors.initials: R
authors.lastname: Kanesvaran
authors.forename: Chee Keong
authors.initials: CK
authors.lastname: Toh
authors.forename: Daniela
authors.initials: D
authors.lastname: Bossi
authors.forename: Isabella
authors.initials: I
authors.lastname: Pallavicini
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Perez-Gracia
authors.forename: Maria Dolores
authors.initials: MD
authors.lastname: Lozano
authors.forename: Valeria
authors.initials: V
authors.lastname: Giandomenico
authors.forename: Ciro
authors.initials: C
authors.lastname: Mercurio
authors.forename: Luisa
authors.initials: L
authors.lastname: Lanfrancone
authors.forename: Nicola
authors.initials: N
authors.lastname: Fazio
authors.forename: Franco
authors.initials: F
authors.lastname: Nole
authors.forename: Bin Tean
authors.initials: BT
authors.lastname: Teh
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Renne
authors.forename: Saverio
authors.initials: S
authors.lastname: Minucci
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D004795:Enzyme Stability; D000071679:Glycogen Synthase Kinase 3 beta / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011758:Pyrroles / Q000494:pharmacology*; D000077210:Sunitinib; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D007211:Indoles; C579095:MCL1 protein, human; D046912:Multiprotein Complexes; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011758:Pyrroles; C546842:MTOR protein, human; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D000077210:Sunitinib