Clinic of Hematology, Department of Internal Medicine, University of Genoa, Genoa, Italy.
IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
Blood Adv. 2020 Sep 22;4(18):4312-4326. doi: 10.1182/bloodadvances.2020001639.
Metabolic reprogramming is emerging as a cancer vulnerability that could be therapeutically exploitable using different approaches, including amino acid depletion for those tumors that rely on exogenous amino acids for their maintenance. ʟ-Asparaginase (ASNase) has contributed to a significant improvement in acute lymphoblastic leukemia outcomes; however, toxicity and resistance limit its clinical use in other tumors. Here, we report that, in multiple myeloma (MM) cells, the DNA methylation status is significantly associated with reduced expression of ASNase-related gene signatures, thus suggesting ASNase sensitivity for this tumor. Therefore, we tested the effects of ASNase purified from Erwinia chrysanthemi (Erw-ASNase), combined with the next-generation proteasome inhibitor (PI) carfilzomib. We observed an impressive synergistic effect on MM cells, whereas normal peripheral blood mononuclear cells were not affected. Importantly, this effect was associated with increased reactive oxygen species (ROS) generation, compounded mitochondrial damage, and Nrf2 upregulation, regardless of the c-Myc oncogenic-specific program. Furthermore, the cotreatment resulted in genomic instability and DNA repair mechanism impairment via increased mitochondrial oxidative stress, which further enhanced its antitumor activity. Interestingly, carfilzomib-resistant cells were found to be highly dependent on amino acid starvation, as reflected by their higher sensitivity to Erw-ASNase treatment compared with isogenic cells. Overall, by affecting several cellular programs, Erw-ASNase makes MM cells more vulnerable to carfilzomib, providing proof of concept for clinical use of this combination as a novel strategy to enhance PI sensitivity in MM patients.
代谢重编程正在成为癌症的一个弱点，可以通过不同的方法进行治疗，包括对那些依赖外源性氨基酸维持的肿瘤进行氨基酸耗竭。L-天冬酰胺酶（ASNase）已显著改善急性淋巴细胞白血病的治疗效果；然而，毒性和耐药性限制了其在其他肿瘤中的临床应用。在这里，我们报告在多发性骨髓瘤（MM）细胞中，DNA 甲基化状态与 ASNase 相关基因特征的表达降低显著相关，这表明 ASNase 对这种肿瘤敏感。因此，我们测试了从欧文氏菌（Erwinia chrysanthemi）中纯化的 ASNase（Erw-ASNase）与下一代蛋白酶体抑制剂（PI）卡非佐米联合使用的效果。我们观察到对 MM 细胞有显著的协同作用，而正常外周血单核细胞不受影响。重要的是，这种效应与活性氧（ROS）生成增加、线粒体损伤加剧和 Nrf2 上调有关，与 c-Myc 致癌特异性程序无关。此外，这种联合治疗通过增加线粒体氧化应激导致基因组不稳定性和 DNA 修复机制受损，进一步增强了其抗肿瘤活性。有趣的是，发现卡非佐米耐药细胞对氨基酸饥饿高度依赖，这反映在它们对 Erw-ASNase 治疗的敏感性高于同源细胞。总的来说，Erw-ASNase 通过影响几种细胞程序使 MM 细胞更容易受到卡非佐米的影响，为该组合作为一种增强 MM 患者 PI 敏感性的新策略的临床应用提供了概念验证。
