Panda Prashanta Kumar, Paschoalini Mafra Ana Carolina, Bastos Alliny C S, Cao Li, Serra Bonet Maria, Brashears Caitlyn B, Chen Ethan Yang, Benedict-Hamilton Heather M, Ehrhardt William, Bomalaski John, Dehner Carina, Rogers Leonard C, Oyama Toshinao, Van Tine Brian A
Division of Medical Oncology, Department of Medicine, School of Medicine, Washington University in St. Louis, St. Louis, Missouri.
Department of Orthopaedic, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China.
Clin Cancer Res. 2025 Apr 1;31(7):1333-1345. doi: 10.1158/1078-0432.CCR-24-2548.
Argininosuccinate synthetase 1 (ASS1) silencing in carcinomas and sarcomas leads to a dependence on extracellular arginine for survival. Arginine deprivation therapies, such as PEGylated arginine deiminase (ADI-PEG20), have shown limited effectiveness, which may be due to underlying mechanisms that inhibit apoptosis.
The effects of ADI-PEG20 on cell-cycle regulation, apoptosis, and BCL-XL-mediated survival pathways in ASS1-deficient cancer cells were determined. The mechanism of cell death protection was determined by assessing caspase and PARP cleavage, CDK2 activity, MCL1 expression, and the interactions among BCL-XL, BAX, and BAK. In vitro synergy was determined, and in vivo efficacy was modeled.
Treatment with ADI-PEG20 led to reduced CDK2 activity and inhibited cell-cycle progression but did not induce significant cell death. BCL-XL was found to bind to BAX and BAK, preventing the initiation of apoptosis despite arginine starvation. Inhibition of BCL-XL allowed proapoptotic BAX and BAK to initiate the intrinsic apoptosis pathway, leading to increased cell death. This was found to be synergistic in vitro and efficacious in combination in vivo.
The study identifies BCL-XL as a key factor limiting the efficacy of arginine starvation therapies. Combining BCL-XL inhibitors with arginine deprivation strategies may overcome this resistance and enhance therapeutic outcomes. These findings provide a strong preclinical rationale for testing this combination approach in phase 1 clinical trials for ASS1-deficient cancers.
精氨酸琥珀酸合成酶1（ASS1）在癌和肉瘤中的沉默导致其生存依赖细胞外精氨酸。精氨酸剥夺疗法，如聚乙二醇化精氨酸脱亚氨酶（ADI-PEG20），已显示出有限的有效性，这可能是由于抑制细胞凋亡的潜在机制。
确定ADI-PEG20对ASS1缺陷癌细胞的细胞周期调控、细胞凋亡和BCL-XL介导的生存途径的影响。通过评估半胱天冬酶和PARP裂解、CDK2活性、MCL1表达以及BCL-XL、BAX和BAK之间的相互作用来确定细胞死亡保护机制。确定体外协同作用，并建立体内疗效模型。
ADI-PEG20处理导致CDK2活性降低并抑制细胞周期进程，但未诱导明显的细胞死亡。发现BCL-XL与BAX和BAK结合，尽管精氨酸饥饿但仍阻止细胞凋亡的启动。抑制BCL-XL可使促凋亡的BAX和BAK启动内源性凋亡途径，导致细胞死亡增加。这在体外具有协同作用，在体内联合使用有效。
该研究确定BCL-XL是限制精氨酸饥饿疗法疗效的关键因素。将BCL-XL抑制剂与精氨酸剥夺策略相结合可能克服这种耐药性并提高治疗效果。这些发现为在ASS1缺陷癌症的1期临床试验中测试这种联合方法提供了强有力的临床前理论依据。
