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L-Ascorbic acid preferentially kills KRAS mutant pancreatic cancer cells through DNA damage

Hye-Lim Jang1,2, Seung Tae Kim1, Jung Yong Hong1

  • 1Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro Gangnam-gu, Seoul, 06351, Korea.

Scientific Reports
|July 2, 2025
PubMed

Insights

High-dose L-ascorbic acid (AA) effectively inhibits pancreatic cancer (PC) growth, particularly in KRAS G12D-mutant cells, by disrupting glycolysis and causing DNA damage. This suggests AA as a potential novel therapeutic for specific PC patient subsets.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Pancreatic cancer (PC) remains a leading cause of cancer mortality worldwide, with limited treatment success for existing immunotherapies and targeted agents.
  • Novel therapeutic strategies are urgently needed for PC, especially for patients with KRAS mutations, which are common in this disease.
  • High-dose L-ascorbic acid (AA) is explored for its potential to selectively target cancer cells by disrupting redox homeostasis.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying the anti-cancer effects of high-dose L-ascorbic acid (AA) in pancreatic cancer (PC) cells.
  • To identify specific PC patient subsets, particularly those with KRAS mutations, who may benefit from AA therapy.
  • To explore the synergistic potential of AA with DNA-damaging agents in preclinical PC models.

Main Methods:

  • Preclinical evaluation of AA cytotoxicity in a panel of human PC cell lines and patient-derived cells (PDCs).
  • Mechanistic studies involving assessment of glycolysis inhibition, GAPDH inactivation, and DNA damage induction by AA.
  • Investigating the synergy between AA and AZD6738, and AA's effect on DNA damage response (DDR) in BRCA-mutant PC cells.

Main Results:

  • AA demonstrated significant inhibition of growth in KRAS G12D-mutant PC cells.
  • AA selectively inhibited glycolysis via GAPDH inactivation and induced DNA damage in KRAS G12D-mutant PC cells.
  • AA showed synergistic effects with AZD6738 and enhanced DNA damage response in BRCA-mutant PC cells, including in PDCs.

Conclusions:

  • KRAS G12D mutation status identifies a promising subset of pancreatic cancer patients for AA therapy.
  • AA exhibits antitumor activity in PC by targeting glycolysis and inducing DNA damage, offering a novel therapeutic avenue.
  • DDR-defective subsets, including BRCA1/2 mutants, represent potential candidates for AA-based combination therapies.
Keywords:
DNA damageKRASL-Ascorbic acidPancreatic cancer

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