Endogenous arginase 2 as a biomarker for PEGylated arginase 1 treatment in squamous cell lung carcinoma xenograft models

Abstract

Background: Arginine depletion induced by PEGylated arginase 1 (BCT-100, PEG-BCT-100 or rhArg1peg5000) has shown promising anticancer effects among arginine auxotrophic cancers that are deficient in argininosuccinate synthetase (ASS1) and ornithine transcarbamylase (OTC). High endogenous arginase 2 (ARG2) was previously found in human lung cancers. Although high ARG2 does not induce immunosuppression nor affect disease progression, it may potentially affect the efficacy of PEGylated arginase 1 treatment. ARG2 was highly expressed in H520 squamous cell lung carcinoma (lung SCC) xenograft while undetectable in SK-MES-1 lung SCC xenograft. We postulated that high endogenous ARG2 expression might hamper anticancer effect of PEGylated arginase 1 in lung SCC. Methods: The in vivo effect of PEGylated arginase 1 was studied using 2 lung SCC xenograft models (SK-MES-1 and H520). Protein expression, arginine concentration and apoptosis were investigated by Western blot, ELISA and TUNEL assay respectively. Results: PEGylated arginase 1 (60 mg/kg) suppressed tumor growth in SK-MES-1 but not in H520 xenograft. ASS1 was highly expressed in SK-MES-1 xenograft while expression of OTC remained low in both xenografts. Serum arginine level was decreased significantly by PEGylated arginase 1 in both xenograft models. On the other hand, intratumoral arginine level was reduced by PEGylated arginase 1 treatment in SK-MES-1 xenograft only. In H520 xenograft, intratumoral arginine level in control arm was already very low which could not be further lowered in PEGylated arginase 1 treatment arms. G1 arrest was indirectly evidenced by downregulation of cyclin A2, B1, D3, E1 and CDK4 with PEGylated arginase 1 in SK-MES-1 xenograft only. Moreover, suppression of proliferation factor Ki67 and activation of apoptosis were induced by PEGylated arginase 1 in SK-MES-1 xenograft only. Conclusion: PEGylated arginase 1 treatment was effective in lung SCC xenograft with low endogenous ARG2 expression. High endogenous ARG2 level may explain low intratumoral arginine level in lung SCC xenograft. ARG2 may serve as an additional predictive biomarker, other than ASS1 and OTC, in PEGylated arginase 1 treatment in lung SCC. Acknowledgment: This research was supported by Hong Kong Anti-Cancer Society, HKSAR.