TY - JOUR
T1 - Therapeutic Assessment of Targeting ASNS Combined with l -Asparaginase Treatment in Solid Tumors and Investigation of Resistance Mechanisms
AU - Apfel, Verena
AU - Begue, Damien
AU - Cordo', Valentina
AU - Holzer, Laura
AU - Martinuzzi, Laetitia
AU - Buhles, Alexandra
AU - Kerr, Grainne
AU - Barbosa, Ines
AU - Naumann, Ulrike
AU - Piquet, Michelle
AU - Ruddy, David
AU - Weiss, Andreas
AU - Ferretti, Stephane
AU - Almeida, Reinaldo
AU - Bonenfant, Debora
AU - Tordella, Luca
AU - Galli, Giorgio G.
N1 - Publisher Copyright:
© 2021 American Chemical Society.
PY - 2021/2/12
Y1 - 2021/2/12
N2 - 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 asparagine (Annu. Rev. Biochem. 2006, 75 (1), 629-654). l-Asparaginase efficacy in solid tumors is limited by dose-related toxicities (OncoTargets and Therapy 2017, pp 1413-1422). Large-scale loss of function genetic in vitro screens identified ASNS as a cancer dependency in several solid malignancies (Cell 2017, 170 (3), 564-576.e16. Cell 2017, 170 (3), 577-592.e10). 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 the face of asparagine deprivation, prompting us to characterize such a 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 a resistance mechanism is elicited by a dual axis: GCN2-ATF4 aimed at restoring amino acid 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.
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 asparagine (Annu. Rev. Biochem. 2006, 75 (1), 629-654). l-Asparaginase efficacy in solid tumors is limited by dose-related toxicities (OncoTargets and Therapy 2017, pp 1413-1422). Large-scale loss of function genetic in vitro screens identified ASNS as a cancer dependency in several solid malignancies (Cell 2017, 170 (3), 564-576.e16. Cell 2017, 170 (3), 577-592.e10). 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 the face of asparagine deprivation, prompting us to characterize such a 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 a resistance mechanism is elicited by a dual axis: GCN2-ATF4 aimed at restoring amino acid 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.
KW - ASNS
KW - asparaginase
KW - asparagine
KW - melanoma
KW - proteomics
UR - http://www.scopus.com/inward/record.url?scp=85100039648&partnerID=8YFLogxK
U2 - 10.1021/acsptsci.0c00196
DO - 10.1021/acsptsci.0c00196
M3 - Article
AN - SCOPUS:85100039648
SN - 2575-9108
VL - 4
SP - 327
EP - 337
JO - ACS Pharmacology and Translational Science
JF - ACS Pharmacology and Translational Science
IS - 1
ER -