Philips Institute for Oral Health Research, VCU School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298.
Center for Cancer Research, Massachusetts General Hospital Cancer Center, Boston, MA 02129.
Proc Natl Acad Sci U S A. 2021 Mar 30;118(13). doi: 10.1073/pnas.2009620118.
-amplified neuroblastoma is a lethal subset of pediatric cancer. MYCN drives numerous effects in the cell, including metabolic changes that are critical for oncogenesis. The understanding that both compensatory pathways and intrinsic redundancy in cell systems exists implies that the use of combination therapies for effective and durable responses is necessary. Additionally, the most effective targeted therapies exploit an "Achilles' heel" and are tailored to the genetics of the cancer under study. We performed an unbiased screen on select metabolic targeted therapy combinations and correlated sensitivity with over 20 subsets of cancer. We found that -amplified neuroblastoma is hypersensitive to the combination of an inhibitor of the lactate transporter MCT1, AZD3965, and complex I of the mitochondrion, phenformin. Our data demonstrate that MCT4 is highly correlated with resistance to the combination in the screen and lowly expressed in -amplified neuroblastoma. Low MCT4 combines with high expression of the MCT2 and MCT1 chaperone CD147 in -amplified neuroblastoma, altogether conferring sensitivity to the AZD3965 and phenformin combination. The result is simultaneous disruption of glycolysis and oxidative phosphorylation, resulting in dramatic disruption of adenosine triphosphate (ATP) production, endoplasmic reticulum stress, and cell death. In mouse models of -amplified neuroblastoma, the combination was tolerable at concentrations where it shrank tumors and did not increase white-blood-cell toxicity compared to single drugs. Therefore, we demonstrate that a metabolic combination screen can identify vulnerabilities in subsets of cancer and put forth a metabolic combination therapy tailored for -amplified neuroblastoma that demonstrates efficacy and tolerability in vivo.
扩增神经母细胞瘤是小儿癌症的一种致命亚型。MYCN 在细胞中驱动许多效应，包括对致癌至关重要的代谢变化。人们认识到细胞系统中既存在代偿途径又存在内在冗余，这意味着需要使用联合疗法来获得有效和持久的反应。此外，最有效的靶向疗法利用“阿喀琉斯之踵”，并根据所研究癌症的遗传学进行定制。我们对选定的代谢靶向治疗联合进行了无偏筛选，并将敏感性与 20 多种癌症亚型相关联。我们发现，扩增神经母细胞瘤对乳酸转运蛋白 MCT1 的抑制剂 AZD3965 和线粒体复合物 I 的抑制剂苯乙双胍的组合非常敏感。我们的数据表明，MCT4 与筛选中的组合耐药性高度相关，并且在扩增神经母细胞瘤中表达水平较低。低 MCT4 与 MCT2 和 MCT1 伴侣 CD147 的高表达相结合，共同赋予了对 AZD3965 和苯乙双胍组合的敏感性。结果是糖酵解和氧化磷酸化同时受到破坏，导致三磷酸腺苷 (ATP) 产生、内质网应激和细胞死亡的急剧破坏。在扩增神经母细胞瘤的小鼠模型中，与单一药物相比，该组合在缩小肿瘤且不增加白细胞毒性的浓度下是可耐受的。因此，我们证明代谢组合筛选可以识别癌症亚群中的脆弱性，并提出了针对扩增神经母细胞瘤的代谢联合治疗方法，该方法在体内显示出疗效和耐受性。
