Lung Cancer: Targets and Therapy (Sep 2022)
Arginine Deprivation in SCLC: Mechanisms and Perspectives for Therapy
Abstract
Joséphine Carpentier,1 Iuliia Pavlyk,1 Uma Mukherjee,2 Peter E Hall,2 Peter W Szlosarek1,2 1Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK; 2Department of Medical Oncology, Barts Health NHS Trust, St. Bartholomew’s Hospital, London, EC1A 7BE, UKCorrespondence: Peter W Szlosarek, Centre for Molecular Oncology, Queen Mary University of London, Charterhouse Square, London, EC1M 6BG, United Kingdom, Tel +44 0 20 7882 3559, Fax +44 0 20 7882 3884, Email [email protected]: Arginine deprivation has gained increasing traction as a novel and safe antimetabolite strategy for the treatment of several hard-to-treat cancers characterised by a critical dependency on arginine. Small cell lung cancer (SCLC) displays marked arginine auxotrophy due to inactivation of the rate-limiting enzyme argininosuccinate synthetase 1 (ASS1), and as a consequence may be targeted with pegylated arginine deiminase or ADI-PEG20 (pegargiminase) and human recombinant pegylated arginases (rhArgPEG, BCT-100 and pegzilarginase). Although preclinical studies reveal that ASS1-deficient SCLC cell lines are highly sensitive to arginine-degrading enzymes, there is a clear disconnect with the clinic with minimal activity seen to date that may be due in part to patient selection. Recent studies have explored resistance mechanisms to arginine depletion focusing on tumor adaptation, such as ASS1 re-expression and autophagy, stromal cell inputs including macrophage infiltration, and tumor heterogeneity. Here, we explore how arginine deprivation may be combined strategically with novel agents to improve SCLC management by modulating resistance and increasing the efficacy of existing agents. Moreover, recent work has identified an intriguing role for targeting arginine in combination with PD-1/PD-L1 immune checkpoint inhibitors and clinical trials are in progress. Thus, future studies of arginine-depleting agents with chemoimmunotherapy, the current standard of care for SCLC, may lead to enhanced disease control and much needed improvements in long-term survival for patients.Keywords: small cell lung cancer, SCLC, arginine, argininosuccinate synthase 1, ASS1, arginine deprivation, tumor microenvironment, immunotherapy
