A metabolic synthetic lethal strategy with arginine deprivation and chloroquine leads to cell death in ASS1-deficient sarcomas

Abstract

Sarcomas comprise a large heterogeneous group of mesenchymal cancers with limited therapeutic options. When treated with standard cytotoxic chemotherapies, many sarcomas fail to respond completely and rapidly become treatment resistant. A major problem in the investigation and treatment of sarcomas is the fact that no single gene mutation or alteration has been identified among the diverse histologic subtypes. We searched for therapeutically druggable targets that are common to a wide range of histologies and hence could provide alternatives to the conventional chemotherapy. Seven hundred samples comprising 45 separate histologies were examined. We found that almost 90% were arginine auxotrophs, as the expression of argininosuccinate synthetase 1 was lost or significantly reduced. Arginine auxotrophy confers sensitivity to arginine deprivation, leading temporarily to starvation and ultimately to cell survival or death under different circumstances. We showed that, in sarcoma, arginine deprivation therapy with pegylated arginine deiminase (ADI-PEG20) maintains a prolonged state of arginine starvation without causing cell death. However, when starvation was simultaneously prolonged by ADI-PEG20 while inhibited by the clinically available drug chloroquine, sarcoma cells died via necroptosis and apoptosis. These results have revealed a novel metabolic vulnerability in sarcomas and provided the basis for a well-tolerated alternative treatment strategy, potentially applicable to up to 90% of the tumors, regardless of histology.

Arginine-Depleting Enzymes – An Increasingly Recognized Treatment Strategy for Therapy-Refractory Malignancies

“…Tumor cells re-acquire de novo arginine biosynthesis capabilities by ASS1 re-expression [73,77]. It is worth noting that metabolic changes are mostly negligible between ADI-PEG20 treated and untreated cells, providing further evidence for resistance development.…”

Targeting Metabolism for Cancer Therapy

“…Whether some tumors are more dependent on loss of ASS1 expression to proliferate is an area of active investigation, as these may be more responsive to arginine depleting drugs. The combination of arginine depletion with other therapies might also limit resistance, and the identification of synthetic lethal targets with ASS1-loss is another approach being evaluated to increase the clinical efficacy of therapies that deplete circulating arginine (Bean et al, 2016; Kremer et al, 2017; Locke et al, 2016). …”

Immune checkpoint inhibitors: The linchpins of modern immunotherapy

“…In sarcomas, there has been interest in harnessing tumor metabolism. Nearly 90% of soft tissue sarcomas are deficient in argininosuccinate synthase 1 (ASS1) due to epigenetic silencing by an unknown mechanism . ASS1 encodes the rate‐limiting enzyme in the urea cycle that is responsible for biosynthesis of arginine.…”