title: The mTORC1/2 Inhibitor AZD8055 Strengthens the Efficiency of the MEK Inhibitor Trametinib to Reduce the Mcl-1/[Bim and Puma] ratio and to Sensitize Ovarian Carcinoma Cells to ABT-737.
abstract: The identification of novel therapeutic strategies is an important urgent requirement for the clinical management of ovarian cancer, which remains the leading cause of death from gynecologic cancer. Several studies have shown that the antiapoptotic proteins Bcl-xLand Mcl-1, as well as the proapoptotic protein Bim, are key elements to be modulated to kill ovarian cancer cells. Pharmacologic inhibition of Bcl-xLis possible by using BH3-mimetic molecules like ABT-737. However, inhibition of Mcl-1 and/or promotion of its BH3-only partners (including Bim, Puma, and Noxa) remains a challenge that may be achieved by modulating the signaling pathways upstream. This study sought whether AZD8055-induced mTOR inhibition and/or trametinib-induced MEK inhibition could modulate Mcl-1 and its partners to decrease the Mcl-1/BH3-only ratio and thus sensitize various ovarian cancer cell lines to ABT-737. AZD8055 treatment inhibited Mcl-1 and increased Puma expression but did not induce massive apoptosis in combination with ABT-737. In contrast, trametinib, which decreased the Mcl-1/BH3-only protein ratio by upregulating Puma and dephosphorylated active Bim, sensitized IGROV1-R10 and OVCAR3 cells to ABT-737. Adding AZD8055 to trametinib further reduced the Mcl-1/BH3-only protein ratio and triggered apoptosis without ABT-737 in IGROV1-R10 cells. Moreover, the AZD8055/trametinib association highly sensitized all cell lines including SKOV3 to ABT-737, the induced dephosphorylated Bim being crucial in this sensitization. Finally, the three-drug combination was also very efficient when replacing AZD8055 by the pan-Akt inhibitor MK-2206. This study thus proposes original multitargeted strategies and may have important implications for the design of novel approaches for ovarian cancer treatment. Mol Cancer Ther; 16(1); 102-15. ©2016 AACR.
authors.affiliation: Normandie Université, UNICAEN, INSERM U1199 (BioTICLA), Centre François Baclesse "Biology and Innovative Therapeutics for Locally Agressive Cancers" (BioTICLA), Caen, France.|Comprehensive Cancer Centre François Baclesse, UNICANCER, Caen, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Pétigny-Lechartier
authors.affiliation: Normandie Université, UNICAEN, INSERM U1199 (BioTICLA), Centre François Baclesse "Biology and Innovative Therapeutics for Locally Agressive Cancers" (BioTICLA), Caen, France.|Comprehensive Cancer Centre François Baclesse, UNICANCER, Caen, France.
authors.forename: Charlène
authors.initials: C
authors.lastname: Duboc
authors.affiliation: Normandie Université, UNICAEN, INSERM U1199 (BioTICLA), Centre François Baclesse "Biology and Innovative Therapeutics for Locally Agressive Cancers" (BioTICLA), Caen, France.|Comprehensive Cancer Centre François Baclesse, UNICANCER, Caen, France.
authors.forename: Abdelghani
authors.initials: A
authors.lastname: Jebahi
authors.affiliation: Normandie Université, UNICAEN, INSERM U1199 (BioTICLA), Centre François Baclesse "Biology and Innovative Therapeutics for Locally Agressive Cancers" (BioTICLA), Caen, France.|Comprehensive Cancer Centre François Baclesse, UNICANCER, Caen, France.
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Louis
authors.affiliation: Normandie Université, UNICAEN, INSERM U1199 (BioTICLA), Centre François Baclesse "Biology and Innovative Therapeutics for Locally Agressive Cancers" (BioTICLA), Caen, France.|Comprehensive Cancer Centre François Baclesse, UNICANCER, Caen, France.
authors.forename: Edwige
authors.initials: E
authors.lastname: Abeilard
authors.affiliation: Normandie Université, UNICAEN, INSERM U1199 (BioTICLA), Centre François Baclesse "Biology and Innovative Therapeutics for Locally Agressive Cancers" (BioTICLA), Caen, France.|Comprehensive Cancer Centre François Baclesse, UNICANCER, Caen, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Denoyelle
authors.affiliation: Normandie Université, UNICAEN, INSERM U1199 (BioTICLA), Centre François Baclesse "Biology and Innovative Therapeutics for Locally Agressive Cancers" (BioTICLA), Caen, France.|Comprehensive Cancer Centre François Baclesse, UNICANCER, Caen, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Gauduchon
authors.affiliation: Normandie Université, UNICAEN, INSERM U1199 (BioTICLA), Centre François Baclesse "Biology and Innovative Therapeutics for Locally Agressive Cancers" (BioTICLA), Caen, France.|Comprehensive Cancer Centre François Baclesse, UNICANCER, Caen, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Poulain
authors.affiliation: Normandie Université, UNICAEN, INSERM U1199 (BioTICLA), Centre François Baclesse "Biology and Innovative Therapeutics for Locally Agressive Cancers" (BioTICLA), Caen, France. m.villedieu@baclesse.unicancer.fr.|Comprehensive Cancer Centre François Baclesse, UNICANCER, Caen, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Villedieu
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11 / Q000378:metabolism; D001713:Biphenyl Compounds / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D009025:Morpholines / Q000494:pharmacology*; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D011728:Pyridones / Q000494:pharmacology*; D011744:Pyrimidinones / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
chemical_list: C501332:ABT-737; D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; D000072224:Bcl-2-Like Protein 11; D001713:Biphenyl Compounds; D009025:Morpholines; D046912:Multiprotein Complexes; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011728:Pyridones; D011744:Pyrimidinones; D013449:Sulfonamides; C560077:trametinib; C546624:(5-(2,4-bis((3S)-3-methylmorpholin-4-yl)pyrido(2,3-d)pyrimidin-7-yl)-2-methoxyphenyl)methanol; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases