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|Ref Type||Journal Article|
|Authors||Pétigny-Lechartier C, Duboc C, Jebahi A, Louis MH, Abeilard E, Denoyelle C, Gauduchon P, Poulain L, Villedieu M|
|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.|
|Journal||Molecular cancer therapeutics|
|Abstract Text||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-xL and Mcl-1, as well as the proapoptotic protein Bim, are key elements to be modulated to kill ovarian cancer cells. Pharmacologic inhibition of Bcl-xL is 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.|
|Molecular Profile||Treatment Approach|
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|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||ovarian cancer||not applicable||ABT-737 + MK2206 + Trametinib||Preclinical - Cell culture||Actionable||In a preclinical study, the combination of MK2206 and Mekinist (trametinib) enhanced the sensitivity of ovarian cancer cells to ABT-737 in culture, resulting in decreased cell viability (PMID: 27980105).||27980105|
|Unknown unknown||ovarian cancer||not applicable||ABT-737 + AZD8055 + Trametinib||Preclinical - Cell culture||Actionable||In a preclinical study, the combination of AZD8055 and Mekinist (trametinib) enhanced the sensitivity of ovarian cancer cells to ABT-737 in culture, resulting in greater apoptotic activity and cell cycle arrest when compared to Mekinist (trametinib) alone (PMID: 27980105).||27980105|
|Unknown unknown||ovarian cancer||not applicable||ABT-737 + Dactolisib + Trametinib||Preclinical - Cell culture||Actionable||In a preclinical study, the combination of BEZ235 and Mekinist (trametinib) enhanced the sensitivity of ovarian cancer cells to ABT-737 in culture, resulting in decreased cell viability (PMID: 27980105).||27980105|