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Argininosuccinate synthetase (ASS) deficiency in high-grade pulmonary neuroendocrine carcinoma: an opportunity for personalized targeted therapy

Abstract

Purpose

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.

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Conflict of interest

JSB is a stock owner and employee of the Polaris Group, Inc., which produces ADI-PEG 20. Other authors declare no conflicts of interest.

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Correspondence to Ann E. Walts.

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Walts, A.E., Bomalaski, J.S., Ines, D. et al. Argininosuccinate synthetase (ASS) deficiency in high-grade pulmonary neuroendocrine carcinoma: an opportunity for personalized targeted therapy. J Cancer Res Clin Oncol 141, 1363–1369 (2015). https://doi.org/10.1007/s00432-014-1904-z

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Keywords

  • Argininosuccinate synthetase (ASS)
  • Pegylated arginine deiminase (ADI-PEG20)
  • Neuroendocrine carcinoma
  • Small cell lung cancer
  • Large cell neuroendocrine carcinoma