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-x L 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-x L 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 trametinibinduced 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. Ó2016 AACR.

Aspirin sensitizes osimertinib‐resistant NSCLC cells in vitro and in vivo via Bim‐dependent apoptosis induction

“…Then, we detected the key signaling pathways for Bim transcription regulation. We used western blotting to analyze Akt and Erk phosphorylation in PC‐9GROR and H1975‐OR cells treated for 48 h with aspirin, osimertinib, or both (Petigny‐Lechartier et al , 2017; Wu et al , 2016). Erk phosphorylation was strongly inhibited by the combination of aspirin and osimertinib in PC‐9GROR cells but not in H1975‐OR cells.…”

Selective targeting of antiapoptotic BCL‐2 proteins in cancer

“…ABT‐737 exerted single‐agent activity in small cell lung cancer (SCLC) and lymphoma cells and in vitro tumor models. Other laboratories and we thoroughly studied the effects of ABT‐737 on multiple solid and hematological malignancies as single agent or in combination with chemotherapy, radiotherapy, and targeted therapies . The poor oral availability of ABT‐737 led to the development of its orally available analog, ABT‐263 (navitoclax), which paved the way for clinical trials of the first generation of BCL‐2/BCL‐XL inhibitors (Table ).…”

IGF system targeted therapy: Therapeutic opportunities for ovarian cancer

“…This enables Bcl-xL and Bcl-2 to exert their anti-apoptotic function by maintaining the mitochondrial integrity [104]. In addition, signaling via PI3K-AKT or ERK promotes transcription of anti-apoptotic Bcl-2 family member Mcl-1 whereas it inhibits transcription of pro-apoptotic Bcl-2 family members including Bim [105]. Anti-apoptotic Bcl-2 family members Bcl-x L and Mcl-1 and pro-apoptotic Bcl-2 family member Bim are considered important targets in ovarian cancer [105].…”

“…In addition, signaling via PI3K-AKT or ERK promotes transcription of anti-apoptotic Bcl-2 family member Mcl-1 whereas it inhibits transcription of pro-apoptotic Bcl-2 family members including Bim [105]. Anti-apoptotic Bcl-2 family members Bcl-x L and Mcl-1 and pro-apoptotic Bcl-2 family member Bim are considered important targets in ovarian cancer [105]. Recently, it was shown that combined PI3K-AKT and ERK pathway inhibition sensitized ovarian cancer cells to Bcl-x L inhibition [105].…”

“…Anti-apoptotic Bcl-2 family members Bcl-x L and Mcl-1 and pro-apoptotic Bcl-2 family member Bim are considered important targets in ovarian cancer [105]. Recently, it was shown that combined PI3K-AKT and ERK pathway inhibition sensitized ovarian cancer cells to Bcl-x L inhibition [105]. These results indicate that a combination of PI3K-AKT and ERK pathway inhibition, for instance by targeting IGF-1R/IR, with inhibitors of the intrinsic apoptotic pathway may be a valid novel therapeutic strategy for ovarian cancer.…”