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De Novo Serine Synthesis Is a Metabolic Vulnerability That Can Be Exploited to Overcome Sunitinib Resistance in

Manon Teisseire1, Umakant Sahu2,3, Julien Parola1

  • 1Université Nice Côte d'Azur, Institute for Research on Cancer and Aging of Nice (IRCAN) UMR CNRS 7284/U1081, INSERM, Centre Antoine Lacassagne, Nice, France.

Cancer Research
|March 3, 2025
PubMed

Insights

Sunitinib resistance in cancer is linked to increased serine synthesis. Targeting this pathway enhances sunitinib sensitivity, offering new therapeutic strategies for renal cell carcinoma and other cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Metabolic Pathways

Background:

  • Sunitinib is a tyrosine kinase inhibitor effective against advanced renal cell carcinoma (RCC).
  • A significant portion of patients (30%) develop resistance to sunitinib, necessitating research into resistance mechanisms.
  • Understanding resistance can lead to strategies for improving sunitinib efficacy.

Purpose of the Study:

  • To investigate the molecular mechanisms behind sunitinib resistance in renal cell carcinoma.
  • To identify potential therapeutic targets to overcome sunitinib resistance.
  • To explore the role of metabolic reprogramming in sunitinib resistance.

Main Methods:

  • Analysis of metabolic shifts in RCC cells following sunitinib treatment.
  • Investigation of the GCN2-ATF4 stress response pathway.
  • Inhibition of key serine synthesis enzymes (e.g., phosphoglycerate dehydrogenase, phosphoserine aminotransferase 1).
  • Assessment of sunitinib sensitivity in resistant cancer cells.

Main Results:

  • Sunitinib treatment induces a metabolic shift towards increased serine synthesis in RCC cells.
  • The GCN2-ATF4 pathway mediates the link between sunitinib and elevated serine production.
  • Increased serine biosynthesis supports nucleotide synthesis, proliferation, migration, and invasion.
  • Inhibiting serine synthesis enzymes resensitized resistant cells to sunitinib.
  • Serine synthesis activation was observed in multiple cancer types treated with sunitinib.

Conclusions:

  • The de novo serine synthesis pathway is a key adaptive response to sunitinib therapy.
  • Targeting serine biosynthesis represents a promising strategy to overcome sunitinib resistance.
  • This metabolic dependency offers therapeutic opportunities across various cancer types.

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