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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics

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Cancer Biology and Translational Studies

Exploiting Arginine Auxotrophy with Pegylated Arginine Deiminase (ADI-PEG20) to Sensitize Pancreatic Cancer to Radiotherapy via Metabolic Dysregulation

Pankaj K. Singh, Amit A. Deorukhkar, Bhanu P. Venkatesulu, Xiaolin Li, Ramesh Tailor, John S. Bomalaski and Sunil Krishnan
Pankaj K. Singh
Department of Experimental Radiation Oncology, MD Anderson Cancer Center, Houston, Texas.
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Amit A. Deorukhkar
Department of Experimental Radiation Oncology, MD Anderson Cancer Center, Houston, Texas.
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Bhanu P. Venkatesulu
Department of Experimental Radiation Oncology, MD Anderson Cancer Center, Houston, Texas.
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Xiaolin Li
Department of Experimental Radiation Oncology, MD Anderson Cancer Center, Houston, Texas.
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Ramesh Tailor
Department of Radiation Physics, MD Anderson Cancer Center, Houston, Texas.
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John S. Bomalaski
Polaris Pharmaceuticals, Inc., San Diego, California.
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Sunil Krishnan
Department of Experimental Radiation Oncology, MD Anderson Cancer Center, Houston, Texas.
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  • For correspondence: skrishnan@mdanderson.org
DOI: 10.1158/1535-7163.MCT-18-0708 Published December 2019
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Abstract

Distinct metabolic vulnerabilities of cancer cells compared with normal cells can potentially be exploited for therapeutic targeting. Deficiency of argininosuccinate synthetase-1 (ASS1) in pancreatic cancers creates auxotrophy for the semiessential amino acid arginine. We explored the therapeutic potential of depleting exogenous arginine via pegylated arginine deiminase (ADI-PEG20) treatment as an adjunct to radiotherapy. We evaluated the efficacy of treatment of human pancreatic cancer cell lines and xenografts with ADI-PEG20 and radiation via clonogenic assays and tumor growth delay experiments. We also investigated potential mechanisms of action using reverse-phase protein array, Western blotting, and IHC and immunofluorescence staining. ADI-PEG20 potently radiosensitized ASS1-deficient pancreatic cancer cells (MiaPaCa-2, Panc-1, AsPc-1, HPAC, and CaPan-1), but not ASS1-expressing cell lines (Bxpc3, L3.6pl, and SW1990). Reverse phase protein array studies confirmed increased expression of proteins related to endoplasmic reticulum (ER) stress and apoptosis, which were confirmed by Western blot analysis. Inhibition of ER stress signaling with 4-phenylbutyrate abrogated the expression of ER stress proteins and reversed radiosensitization by ADI-PEG20. Independent in vivo studies in two xenograft models confirmed significant tumor growth delays, which were associated with enhanced expression of ER stress proteins and apoptosis markers and reduced expression of proliferation and angiogenesis markers. ADI-PEG20 augmented the effects of radiation by triggering the ER stress pathway, leading to apoptosis in pancreatic tumor cells.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Mol Cancer Ther 2019;18:2381–93

  • Received June 27, 2018.
  • Revision received December 5, 2018.
  • Accepted August 2, 2019.
  • Published first August 8, 2019.
  • ©2019 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 18 (12)
December 2019
Volume 18, Issue 12
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Exploiting Arginine Auxotrophy with Pegylated Arginine Deiminase (ADI-PEG20) to Sensitize Pancreatic Cancer to Radiotherapy via Metabolic Dysregulation
Pankaj K. Singh, Amit A. Deorukhkar, Bhanu P. Venkatesulu, Xiaolin Li, Ramesh Tailor, John S. Bomalaski and Sunil Krishnan
Mol Cancer Ther December 1 2019 (18) (12) 2381-2393; DOI: 10.1158/1535-7163.MCT-18-0708

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Exploiting Arginine Auxotrophy with Pegylated Arginine Deiminase (ADI-PEG20) to Sensitize Pancreatic Cancer to Radiotherapy via Metabolic Dysregulation
Pankaj K. Singh, Amit A. Deorukhkar, Bhanu P. Venkatesulu, Xiaolin Li, Ramesh Tailor, John S. Bomalaski and Sunil Krishnan
Mol Cancer Ther December 1 2019 (18) (12) 2381-2393; DOI: 10.1158/1535-7163.MCT-18-0708
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Molecular Cancer Therapeutics
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