Up-regulation of Pro-apoptotic Protein Bim and Down-regulation of Anti-apoptotic Protein Mcl-1 Cooperatively Mediate Enhanced Tumor Cell Death Induced by the Combination of ERK Kinase (MEK) Inhibitor and Microtubule Inhibitor

Abstract

Background: MEK inhibitors enhance apoptosis induction by microtubule inhibitors. Results: MEK and microtubule inhibitors together induced up-regulation of Bim and down-regulation of Mcl-1 in association with prolongation of mitosis. Conclusion:The drug combination tips the balance between pro-and anti-apoptotic signaling toward induction of cell death. Significance: The combination of MEK inhibitors with agents that down-regulate or inactivate anti-apoptotic proteins is a promising anticancer strategy.

Muscle Segment Homeobox Genes Direct Embryonic Diapause by Limiting Inflammation in the Uterus

“…These results implicate that increased proteasome activity in the absence of Msx was to counteract the burden of unfolded/misfolded proteins caused by enhanced translation and ER stress. This is consistent with increased incidence of pseudoimplantation sites with bortezomib (57). Indeed, we found increased population of Bippositive cells and higher Bip levels in bortezomib-treated Msx1/ Msx2 d/d uteri consistent with aggravated ER and proteotoxic stress (Fig.…”

Molecular Pathways: The Basis for Rational Combination Using MEK Inhibitors in KRAS-Mutant Cancers

“…Furthermore, Kawabata and colleagues have suggested, in a preclinical study, an interesting possibility that efficacy of the combination with microtubule inhibitors and MEK inhibitors is largely schedule dependent (44). The study demonstrated that when the microtubule inhibitor was administered first followed by a MEK inhibitor, cell death was observed, but not when the sequence was reversed (44). This observation may be related to the different phases of the cell cycle in which MEK inhibitors and chemotherapy act.…”

“…Microtubule inhibitors, such as taxanes or vinorelbine, can lead to activation of the RAS-ERK pathway, and combining MEK inhibitors with these agents suppressed RAS-mediated signaling and increased the efficacy of the drugs in treatment of cancer (49,50). Furthermore, Kawabata and colleagues have suggested, in a preclinical study, an interesting possibility that efficacy of the combination with microtubule inhibitors and MEK inhibitors is largely schedule dependent (44). The study demonstrated that when the microtubule inhibitor was administered first followed by a MEK inhibitor, cell death was observed, but not when the sequence was reversed (44).…”

“…Although the mechanism(s) of efficacy of the combination with docetaxel and a MEK inhibitor remains unclear, results from preclinical studies provide some intriguing observations (43,44). In a murine study of Kras G12D NSCLC, the combination of docetaxel/selumetinib produced response rates of 92% compared with 30% in docetaxel (tumor volume difference was 43.7%, P ¼ 0.03273), and the combination led to a prolonged PFS compared with docetaxel alone (12 weeks vs. 6 weeks, P ¼ 0.0003) in the murine study (43).…”

The Mutant KRAS Gene Up-regulates BCL-XL Protein via STAT3 to Confer Apoptosis Resistance That Is Reversed by BIM Protein Induction and BCL-XL Antagonism

“…Therefore, up-regulation of BIM may offer the greatest potential to improve therapeutic efficacy. However, the induction of BIM proteins by MEK/ERK inhibition (15,16) can result in BIM being bound and inhibited by anti-apoptotic BCL-2 and/or BCL-XL, which are frequently overexpressed in solid tumors (17). This antagonism may explain the modest apoptotic and largely cytostatic effect of MEK/ERK inhibitors in KRAS mutant tumor xenografts (18) as well as predominantly stable disease in patient studies (6,7).…”