title: Argininosuccinate synthetase (ASS) deficiency in high-grade pulmonary neuroendocrine carcinoma: an opportunity for personalized targeted therapy.
abstract: OBJECTIVE
  Cells deficient in argininosuccinate synthetase (ASS) must absorb the arginine they need for growth from circulating blood. Treatment with pegylated arginine deiminase (ADI-PEG 20) selectively eliminates arginine from the circulation and has shown some efficacy against ASS-deficient tumors including small cell lung cancer (SCLC). We sought to assess ASS expression in a cohort of high-grade pulmonary neuroendocrine carcinomas (PNEC) which include SCLC and large cell neuroendocrine carcinoma (LCNEC).
  
  
  METHODS
  Sixty-nine PNEC (49 SCLC and 20 LCNEC) were retrieved from our pathology archives. Formalin-fixed paraffin-embedded sections of the 54 primary tumors, 15 metastases and appropriate positive and negative controls were immunostained using an ASS-specific monoclonal antibody. Positive staining in <30 % of the tumor was scored as weak; staining in ≥30 % of the tumor was scored as strong. The absence of staining in the tumor was recorded as ASS negative.
  
  
  RESULTS
  58 % of the PNEC including 61.2 % of the SCLC and 50 % of the LCNEC were ASS negative. These ASS-negative tumors included 63 % of the primary and 40 % of the metastatic lesions tested.
  
  
  CONCLUSIONS
  More than 50 % of the high-grade PNEC tested lack immunohistochemically detectable ASS, suggesting that they are auxotrophic for arginine and potential candidates for arginine deprivation therapy. PNEC comprise about 25 % of primary lung cancers and have a 5-year overall survival of only 5-10 %, underscoring the need for new and more effective therapies. Immunostaining for ASS has potential to improve the selection of patients with PNEC for arginine deprivation therapy with ADI-PEG 20.
authors.affiliation: Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA, 90048, USA, walts@cshs.org.
authors.forename: Ann E
authors.initials: AE
authors.lastname: Walts
authors.forename: John S
authors.initials: JS
authors.lastname: Bomalaski
authors.forename: Delma
authors.initials: D
authors.lastname: Ines
authors.forename: Sandra
authors.initials: S
authors.lastname: Orsulic
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001124:Argininosuccinate Synthase / Q000172:deficiency*; D018278:Carcinoma, Neuroendocrine / Q000201:enzymology / Q000473:pathology / Q000628:therapy*; D005260:Female; D006801:Humans; D006867:Hydrolases / Q000627:therapeutic use*; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000201:enzymology / Q000473:pathology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000379:methods*; D060787:Neoplasm Grading; D018579:Patient Selection; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D057285:Precision Medicine / Q000379:methods*; D055752:Small Cell Lung Carcinoma / Q000453:epidemiology / Q000378:metabolism / Q000473:pathology / Q000628:therapy
chemical_list: D011092:Polyethylene Glycols; D006867:Hydrolases; C512527:ADI PEG20; D001124:Argininosuccinate Synthase