Due to the rarity of TP53 mutations in acute lymphoblastic leukemia (ALL), p53 re-activation by antagonism of the p53-MDM2 interaction represents a potential therapeutic strategy for the majority of ALL. Here, we demonstrate the potent antileukemic activity of the MDM2 antagonist idasanutlin in high-risk and relapsed ex vivo coculture models of TP53 wildtype ALL (n = 40). Insufficient clinical responses to monotherapy MDM2 inhibitors in other cancers prompted us to explore optimal drugs for combination therapy. Utilizing high-throughput combination screening of 1971 FDA-approved and clinically advanced compounds, we identified BCL-x_L/BCL-2 inhibitor navitoclax as the most promising idasanutlin combination partner. The idasanutlin-navitoclax combination was synergistically lethal to prognostically-poor, primary-derived and primary patient blasts in ex vivo coculture, and reduced leukemia burden in two very high-risk ALL xenograft models at drug concentrations safely attained in patients; in fact, the navitoclax plasma concentrations were equivalent to those attained in contemporary “low-dose” navitoclax clinical trials. We demonstrate a preferential engagement of cell death over G₁ cell cycle arrest, mechanistically implicating MCL-1-binding pro-apoptotic sensitizer NOXA. The proposed combination of two clinical-stage compounds independently under clinical evaluation for ALL is of high clinical relevance and warrants consideration for the treatment of patients with high-risk and relapsed ALL.

由于急性淋巴细胞白血病 (ALL) 中TP53突变的罕见性，通过拮抗 p53-MDM2 相互作用来重新激活 p53 代表了大多数 ALL 的潜在治疗策略。在这里，我们证明了 MDM2 拮抗剂 idasanutlin 在TP53野生型 ALL ( n  = 40) 的高风险和复发离体共培养模型中具有有效的抗白血病活性。其他癌症对单药 MDM2 抑制剂的临床反应不足，促使我们探索联合治疗的最佳药物。利用对 1971 年 FDA 批准的临床先进化合物的高通量组合筛选，我们确定 BCL-x _L /BCL-2 抑制剂 navitoclax 是最有前途的 idasanutlin 组合伙伴。在离体共培养中，idasanutlin-navitoclax 组合对预后较差的原发性和原发性患者原始细胞具有协同致死作用，并且在患者安全达到的药物浓度下，在两种极高风险 ALL 异种移植模型中减少了白血病负担；事实上，navitoclax 血浆浓度与当代“低剂量”navitoclax 临床试验中达到的浓度相当。我们证明了细胞死亡优先于 G ₁细胞周期停滞，这在机制上暗示了 MCL-1 结合促凋亡敏化剂 NOXA。所提议的两种临床阶段化合物的组合在 ALL 临床评估下独立具有很高的临床相关性，值得考虑用于治疗高危和复发性 ALL 患者。