Editors' ChoiceCancer

Novel drug combination unleashes apoptosis in AML

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Science Translational Medicine  03 Jan 2018:
Vol. 10, Issue 422, eaar7509
DOI: 10.1126/scitranslmed.aar7509

Abstract

The combination of p53 activation and Bcl-2 inhibition reciprocally overcomes apoptosis resistance and leads to synergistic efficacy in acute myeloid leukemia.

Defective apoptosis and increased cell survival, through up-regulation of antiapoptotic Bcl-2 family proteins and inactivation of p53, is a hallmark of cancer, including acute myeloid leukemia (AML). ABT-199 (venetoclax, ABT) is a selective Bcl-2 inhibitor with significant activity in AML; however, up-regulation of Mcl-1, another antiapoptotic protein, confers resistance to ABT. The p53-encoding gene, TP53, is less commonly mutated in AML than other cancers, although p53 activity is impaired by up-regulated MDM2, an E3 ubiquitin ligase that targets MDM2 for proteasomal degradation. MDM2 inhibitors, including RG7388 (idasanutlin, RG), that activate the p53 pathway and promote apoptosis are being clinically developed in AML and other cancers.

Pan and colleagues used an impressive battery of in vitro and in vivo AML models to study whether the combination of p53 activation by RG and Bcl-2 inhibition by ABT could overcome apoptosis resistance to either approach alone. In p53WT, p53mutant, ABT-sensitive, and ABT-resistant AML cell lines, RG was shown to activate p53, induce apoptosis in a p53-dependent manner, overcome Mcl-1–mediated resistance to Bcl-2 inhibition, and lead to synergistic cell death in combination with ABT. Mechanistic studies of RG and ABT synergy demonstrated that p53 activation overcame Mcl-1–mediated resistance to Bcl-2 inhibition by regulating the Ras/Raf/MEK/ERK cascade and GSK3 signaling. This, in turn, promotes Mcl-1 degradation through stabilization of the dual-phosphorylated form of Mcl-1, a target for ubiquitination and proteasomal degradation. Meanwhile, Bcl-2 inhibition reciprocally overcame apoptosis resistance to p53 activation by shifting the cellular response from p21-induced prosurvival G1 arrest to apoptosis. Consistent with the in vitro mechanistic studies, the combination of RG and ABT showed significantly decreased leukemia burden and prolonged survival compared with either RG or ABT alone in a series of in vivo ABT-resistant AML xenograft and patient-derived xenograft mouse models.

These results confirmed the hypothesis that p53 activation combined with Bcl-2 inhibition can overcome resistance to either treatment alone and lead to significant anti-AML efficacy. The bench-to-bedside potential of this work is already being tested in a phase II clinical trial of ABT and RG in AML. Future investigations should evaluate whether these mechanisms potentially extend to other cancers with relatively low rates of p53 mutations and significant dependency on Bcl-2, such as myelodysplastic syndromes and chronic lymphocytic leukemia.

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