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<p>Secondary resistance to the amino-acid–depleting agent L-asparaginase (ASNase) remains poorly understood. Using ASNase-sensitive B-cell lymphoma (BCL) models, we investigate tumor relapse during treatment. Through in vitro and in vivo metabolic profiling, here we show that ASNase triggers a metabolic reprogramming characterized by increased de novo serine biosynthesis driven by phosphoglycerate dehydrogenase (PHGDH). This response mitigates treatment-induced oxidative stress and associated DNA damage, enabling malignant cells to survive. We evidence that ASNase-treated malignant cells exhibit features of replication stress and increase activity of poly(ADP-ribose) polymerase (PARP), revealing a dependence on DNA repair. Combining ASNase with the clinically approved PARP inhibitor Olaparib enhances the antineoplastic effect of each monotherapy in vitro and in vivo. Moreover, this combination shows effectiveness in homologous recombination-proficient colorectal cancer cells, suggesting broader therapeutic potential. Overall, our study identifies tumor metabolic and genomic vulnerabilities induced by ASNase and supports a rational combination strategy using clinically approved drugs.</p>

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Tumor metabolic adaptation induced by L-asparaginase reveals a vulnerability to PARP1/2 inhibitor in B-cell lymphomas

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月27日

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  • Anaïs Aussel,
  • Ivan Nemazanyy,
  • Ashaina Vandenberghe,
  • Pauline Meola,
  • Noémie Dorat,
  • Rachel Paul,
  • Lama Habbouche,
  • Laurie Exposito,
  • Nicolas Nottet,
  • Virginie Petrilli,
  • Edmond Chiche,
  • Nicolas Mounier,
  • Sandrine Marchetti,
  • Cédric Chaveroux,
  • Jean-Ehrland Ricci,
  • Johanna Chiche

摘要

Secondary resistance to the amino-acid–depleting agent L-asparaginase (ASNase) remains poorly understood. Using ASNase-sensitive B-cell lymphoma (BCL) models, we investigate tumor relapse during treatment. Through in vitro and in vivo metabolic profiling, here we show that ASNase triggers a metabolic reprogramming characterized by increased de novo serine biosynthesis driven by phosphoglycerate dehydrogenase (PHGDH). This response mitigates treatment-induced oxidative stress and associated DNA damage, enabling malignant cells to survive. We evidence that ASNase-treated malignant cells exhibit features of replication stress and increase activity of poly(ADP-ribose) polymerase (PARP), revealing a dependence on DNA repair. Combining ASNase with the clinically approved PARP inhibitor Olaparib enhances the antineoplastic effect of each monotherapy in vitro and in vivo. Moreover, this combination shows effectiveness in homologous recombination-proficient colorectal cancer cells, suggesting broader therapeutic potential. Overall, our study identifies tumor metabolic and genomic vulnerabilities induced by ASNase and supports a rational combination strategy using clinically approved drugs.