Data from Discovery and targeting of a noncanonical mechanism of sarcoma resistance to ADI-PEG20 mediated by the microenvironment

• DOI: 10.1158/1078-0432.c.6736752.v3
• Publication Date: 2024-09-16T12:31:21Z
• Authors: Leonard C. Rogers; Jeff C. Kremer; Caitlyn B. Brashears; Zongtao Lin; Zhixian Hu; Alliny C. S. Bastos; Adriana Baker; Nicole Fettig; Dong Zhou; Kooresh I. Shoghi; Carina A. Dehner; John S. A. Chrisi...; John S. Bomalaski; Benjamin A. Garcia; Toshinao Oyama; Eileen P. White; Brian A. Van Tine

<div>Abstract<p>Purpose: Many cancers lack argininosuccinate synthetase 1 (ASS1), the rate limiting enzyme of arginine biosynthesis. This deficiency causes auxotrophy, targetable by extracellular arginine-degrading enzymes such as ADI-PEG20. Long-term tumor resistance has thus far been attributed solely to ASS1 re-expression. study examines role silencing on growth and initiation identifies a noncanonical mechanism resistance, aiming improve clinical responses Experimental Design: Tumor rates were measured for spontaneous <i>Ass1</i> knockout (KO) murine sarcoma model. cell lines generated, deprivation therapy was studied <i>in vitro </i>and<i> in vivo</i>. Results: Conditional KO affected neither nor model, contradicting prevalent idea that confers proliferative advantage. cells grew robustly through starvation vivo, </i>while ADI-PEG20 remained completely lethal vitro</i>, evidence pointed toward novel mediated microenvironment. Co-culture with <i>Ass1</i>-competent fibroblasts rescued macropinocytosis vesicles and/or fragments, followed recycling protein-bound autophagy/lysosomal degradation. Inhibition either or degradation abrogated this support effect vitro</i> Conclusions: Noncanonical, ASS1-independent is driven can be targeted inhibitor imipramine autophagy chloroquine. These safe, widely available drugs should added current trials overcome microenvironmental tumors patient outcomes.</p></div>