Grass, Verena, Begue, Damien, Cordo, Valentina, Holzer, Laura, Martinuzzi-Duboc, Laetitia, Buhles, Alexandra, Kerr, Grainne, Barbosa, Ines, Naumann, Ulrike, Piquet, Michelle, Ruddy, David, Tordella, Luca, Weiss, Andreas, Ferretti, Stephane Raymond, Almeida, Reinaldo, Bonenfant, Debora and Galli, Giorgio (2021) Therapeutic Assessment of Targeting ASNS Combined with l-Asparaginase Treatment in Solid Tumors and Investigation of Resistance Mechanisms. ACS Pharmacology and Translational Sciences.

Abstract

Asparagine deprivation by L-Asparaginase (L-ASNase) is an effective therapeutic strategy in Acute Lymphoblastic Leukemia, with resistance occurring due to upregulation of ASNS,the only human enzyme synthetizing Asparagine1. L-Asparaginase efficacy in solid tumors is limited by dose-related toxicities 2. Large-scale loss of function genetic in vitro screens identified ASNSas a cancer dependency in several solid malignancies 3,4. Here we evaluate the therapeutic potential of targeting ASNS in melanoma cells. While we confirm in-vitro dependency on ASNS silencing, this is largely dispensable for in vivo tumor growth, even in face of asparagine deprivation, suggesting the need to further characterize such pathway to devise novel therapeutic strategies. Using ex vivo quantitative proteome and transcriptome profiling, we characterize the compensatory mechanism elicited by ASNS knockout melanoma cells allowing their survival. Additionally, genome-wide CRISPR screens upon manipulation of aminoacids levels identify BCLXL, MAPK and GCN2 as critical nodes mediating the observed resistance mechanism. Importantly, pharmacological inhibition of such hits synergizes with L-Asparaginase-mediated Asparagine deprivation in ASNS deficient cells suggesting novel potential therapeutic combinations in melanoma.

Item Type:	Article
Date Deposited:	27 Jan 2021 00:45
Last Modified:	27 Jan 2021 00:45
URI:	https://oak.novartis.com/id/eprint/42490