Oops, you're using an old version of your browser so some of the features on this page may not be displaying properly.

MINIMAL Requirements: Google Chrome 24+Mozilla Firefox 20+Internet Explorer 11Opera 15–18Apple Safari 7SeaMonkey 2.15-2.23

Cocktail & Poster Display session

97P - Bcl-xL prevents the arginine starvation induced by PEGylated arginine deiminase (ADI-PEG20) from inducing apoptosis


06 Mar 2023


Cocktail & Poster Display session


Brian Van Tine


Annals of Oncology (2023) 8 (1suppl_2): 100898-100898. 10.1016/esmoop/esmoop100898


B.A. Van Tine1, P. Panda2, L. Rogers2, T. Oyama2

Author affiliations

  • 1 Medical Oncology Department, Washington University School of Medicine in St. Louis, 63108 - St. Louis/US
  • 2 Medical Oncology Department, Washington University School of Medicine in St. Louis, 63110 - St. Louis/US


This content is available to ESMO members and event participants.

Abstract 97P


Multiple clinical trials are using PEGylated arginine deiminase (ADI-PEG20) to induce arginine starvation in cancers that are argininosuccinate synthetase (ASS1) low. ASS1 low tumors include sarcomas, melanomas, non-small cell and small cell lung cancers, triple-negative breast, pancreatic cancer, and many others. While ADI-PEG20 clearly induces an arginine starvation response, no cell death is initiated at a meaningful level. While many studies have seen low levels of apoptosis (<10%), the primary effect of ADI-PEG20 is cytostatic, as tumors metabolically reprogram themselves by upregulating ASS1, gaining the ability to produce arginine.


Cell lines were treated with ADI-PEG20 and A-1331852 (Bcl-xL inhibitor) and monitored for cell death using the Incucyte. CRISPR models confirmed that the Bcl-xL effects of A-1331852 were on target. CDK2 activity, Bcl-xL and Mcl-1 were measured in response to ADI-PEG20 using Wes capillary electrophoresis. These cell lines were grafted into mice and treated with ADI-PEG20 and A-1331852.


Arginine starvation inhibits CDK2, resulting in the loss of Mcl-1 expression. Neither Bcl-2 nor Mcl-1 inhibitors initiated cell death when combined with ADI-PEG20. Dual treatment of Bcl-xL inhibitor A-1331852 with ADI-PEG20 led to mitochondrial BAX levels increasing fivefold, corresponding to a drop in cytoplasmic levels that suggests translocation to the mitochondria. A similar but less dramatic pattern of significant increase in mitochondrial levels was observed with BAK. Inhibition of Bcl-xL with ADI-PEG20 induced CASP3/7 and PARP cleavage, resulting in apoptosis in a panel of ASS1 low cell lines. This was confirmed in vivo.


ADI-PEG20 does not induce cell death as a monotherapy, but the arginine starvation instead results in metabolic adaptation. This begins to explain the lack of efficacy seen in early ADI-PEG20 monotherapy trials. Bcl-xL, but not Mcl-1 or Bcl-2, prevents ADI-PEG20 from inducing apoptosis. Bcl-xL inhibition synergies with ADI-PEG20 to induce apoptosis. This study provides the preclinical rationale for combining ADI-PEG20 with next generation Bcl-xL inhibitors such as the Bcl-xL PROTAC in a phase I clinical trial.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.


Polaris, NIH.


B.A. Van Tine: Financial Interests, Personal, Invited Speaker, Educational Speaker: Targeted Oncology; Financial Interests, Personal, Advisory Board, Also, Travel paid to conference to present abstract: Adaptimmune; Financial Interests, Personal, Invited Speaker, Also attended an Ad Board meeting, Travel was paid to present abstract at conference: GSK; Financial Interests, Personal, Other, Consulting, Also attended and Ad Board meeting, Travel was paid to attend an Ad board meeting: Epizyme; Financial Interests, Personal, Other, Consulting- ADRx working on a cancer project and they are requesting my expertise: ADRx; Financial Interests, Personal, Advisory Board, tenosynovial giant cell tumors (TGCT): Ayala Pharmaceuticals; Financial Interests, Personal, Other, Consulting/Advisor: Cytokinetics; Financial Interests, Personal, Other, Consulting: Bayer; Financial Interests, Personal, Other, 60 minute interview regarding Synovial Sarcoma: Bionest Partners; Financial Interests, Personal, Other, OncLive Virtual Workshop: Intellisphere; Financial Interests, Personal, Advisory Board, Attended Advisory Board Meeting: Apexigen; Financial Interests, Personal, Advisory Board, Attended an Advisory Board Meeting: Daiichi Sankyo, Deciphera Pharmaceuticals; Financial Interests, Personal, Advisory Board, Attended an Advisory Board Meeting: Novartis; Financial Interests, Personal, Advisory Board: Lilly, PTC Therapeutics; Financial Interests, Personal, Invited Speaker, Sigma-2 Receptor Ligands and Therapeutic uses therefor (006766), Modular Platform for Targeted Therapeutic Delivery (006755), Sigma-2 Receptor Ligand Drug Conjugates as Antitumor Compounds, Methods of synthesis and Uses Thereof (014229): Accuronix Therapeutics; Financial Interests, Institutional, Research Grant: Pfizer, Merck, Tracon Pharm, GSK; Non-Financial Interests, Personal, Invited Speaker: Polaris. All other authors have declared no conflicts of interest.

This site uses cookies. Some of these cookies are essential, while others help us improve your experience by providing insights into how the site is being used.

For more detailed information on the cookies we use, please check our Privacy Policy.

Customise settings
  • Necessary cookies enable core functionality. The website cannot function properly without these cookies, and you can only disable them by changing your browser preferences.