RT Journal Article
SR Electronic
T1 Therapeutic assessment of targeting ASNS combined with L-Asparaginase treatment in solid tumors and investigation of resistance mechanisms
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.09.08.287565
DO 10.1101/2020.09.08.287565
A1 Verena Apfel
A1 Damien Begue
A1 Valentina Cordo
A1 Laura Holzer
A1 Laetitia Martinuzzi
A1 Alexandra Buhles
A1 Grainne Kerr
A1 Ines Barbosa
A1 Ulrike Naumann
A1 Michelle Piquet
A1 David Ruddy
A1 Andreas Weiss
A1 Stephane Ferretti
A1 Reinaldo Almeida
A1 Debora Bonenfant
A1 Luca Tordella
A1 Giorgio G. Galli
YR 2020
UL http://biorxiv.org/content/early/2020/09/09/2020.09.08.287565.abstract
AB 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 ASNS as 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, prompting us characterize such resistance mechanism 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. Mechanistically, a genome-wide CRISPR screen revealed that such resistance mechanism is elicited by a dual axis: GCN2-ATF4 aimed at restoring amino acids levels and MAPK-BCLXL to promote survival. Importantly, pharmacological inhibition of such nodes synergizes with L-Asparaginase-mediated Asparagine deprivation in ASNS deficient cells suggesting novel potential therapeutic combinations in melanoma.Competing Interest StatementThe authors have declared no competing interest.