Synthetic Lethality of Combined Bcl-2 Inhibition and p53 Activation in AML: Mechanisms and Superior Antileukemic Efficacy

• Published in: Cancer cell 2017-12, Vol.32 (6), p.748-760.e6
• Main Authors: Pan, Rongqing, Ruvolo, Vivian, Mu, Hong, Leverson, Joel D., Nichols, Gwen, Reed, John C., Konopleva, Marina, Andreeff, Michael
• Format: Article
• Language: English
• Subjects: ABT-199; Animals; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apoptosis - drug effects; apoptosis resistance; Bcl-2; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Cell Line, Tumor; Drug Resistance, Neoplasm - drug effects; Female; G1 arrest; Humans; leukemia; Leukemia, Myeloid, Acute - pathology; MAPK; Mcl-1; MDM2; Mice; Mice, Inbred NOD; Mice, SCID; p53; para-Aminobenzoates - pharmacology; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; Pyrrolidines - pharmacology; RG7388; Sulfonamides - pharmacology; Synthetic Lethal Mutations - drug effects; Tumor Suppressor Protein p53 - metabolism; Xenograft Model Antitumor Assays
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2017.11.003

Evasion of apoptosis is a hallmark of cancer. Bcl-2 and p53 represent two important nodes in apoptosis signaling pathways. We find that concomitant p53 activation and Bcl-2 inhibition overcome apoptosis resistance and markedly prolong survival in three mouse models of resistant acute myeloid leukemia (AML). Mechanistically, p53 activation negatively regulates the Ras/Raf/MEK/ERK pathway and activates GSK3 to modulate Mcl-1 phosphorylation and promote its degradation, thus overcoming AML resistance to Bcl-2 inhibition. Moreover, Bcl-2 inhibition reciprocally overcomes apoptosis resistance to p53 activation by switching cellular response from G1 arrest to apoptosis. The efficacy, together with the mechanistic findings, reveals the potential of simultaneously targeting these two apoptosis regulators and provides a rational basis for clinical testing of this therapeutic approach. •p53 regulates Ras/Raf/MEK/ERK/GSK3 signaling cascade to promote Mcl-1 degradation•Bcl-2 inhibition shifts the outcomes of p53 activation from G1 arrest to apoptosis•p53 activation and Bcl-2 inhibition reciprocally overcome apoptosis resistance•The combination markedly prolongs survival in three mouse models of resistant AML Pan et al. show that p53 activation promotes Mcl-1 degradation, and Bcl-2 inhibition shifts the p53 activation response from G1 arrest to apoptosis. Combining p53 activation and Bcl-2 inhibition overcomes resistance to either alone and provides better therapeutic efficacy in mouse models of acute myeloid leukemia.