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FASN Inhibition Enhances the Efficacy of Chemotherapy in Colorectal Cancer by Inhibiting the DNA Damage Response

Moumita Banerjee1, Yekaterina Y Zaytseva1,2, Ellen M Reusch1

  • 1Markey Cancer Center , University of Kentucky, Lexington, Kentucky.

Cancer Research
|February 9, 2026
PubMed

Insights

Fatty acid synthase (FASN) inhibition in colorectal cancer (CRC) causes DNA damage and impairs repair. Combining FASN inhibitors with chemotherapy and PARP inhibitors offers a promising strategy to prevent tumor recurrence.

Area of Science:

  • Oncology
  • Cancer Metabolism
  • DNA Damage Response

Background:

  • Altered lipid metabolism, particularly de novo lipogenesis regulated by Fatty Acid Synthase (FASN), is a metabolic vulnerability in colorectal cancer (CRC).
  • FASN inhibitors show modest efficacy alone, necessitating combination strategies for improved patient survival.
  • Understanding FASN inhibition's impact on DNA damage and repair is crucial for developing effective CRC therapies.

Purpose of the Study:

  • To investigate the effects of FASN inhibition on DNA damage and the DNA damage response (DDR) in colorectal cancer.
  • To explore combination strategies involving FASN inhibitors, chemotherapy, and PARP inhibitors for CRC treatment.
  • To elucidate the mechanistic basis of FASN inhibition-induced synthetic lethality with PARP inhibitors.

Main Methods:

  • Analysis of patient samples from a TVB-2640 window trial.
  • In vitro studies using colon cancer cell lines and patient-derived organoids.
  • Assessment of DNA damage (DSBs), apoptosis, histone acetylation, ATM expression, CHK2 phosphorylation, and recruitment of BRCA1/ATM to g-H2AX foci.
  • Evaluation of combination therapies in xenograft models.

Main Results:

  • FASN inhibition induced DNA damage but impaired the DNA damage response (DDR) in CRC cells and organoids.
  • FASN inhibition potentiated chemotherapy-induced double-strand DNA breaks (DSBs) and apoptosis by altering histone acetylation.
  • FASN inhibition blocked DDR by decreasing ATM expression and CHK2 phosphorylation, and attenuated BRCA1/ATM recruitment to g-H2AX foci.
  • FASN inhibition induced synthetic lethality with PARP inhibition.
  • Combination of FASN inhibition with irinotecan synergistically reduced tumor growth and relapse in vivo, further enhanced by olaparib maintenance.

Conclusions:

  • FASN inhibition impairs DNA repair mechanisms in colorectal cancer.
  • Combining FASN inhibitors with chemotherapy and PARP inhibitors represents a viable therapeutic strategy to overcome treatment resistance and prevent tumor recurrence in CRC.
  • This approach holds potential for improving long-term survival in colorectal cancer patients.

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