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Enhancing PDAC therapy: Decitabine-olaparib synergy targets KRAS-dependent tumors

Giorgia Anastasio1, Michela Felaco1,2, Alessia Lamolinara3,4

  • 1Institute of Biochemistry and Cellular Biology, National Research Council, Monterotondo-Scalo, 00015 Rome, Italy.

Iscience
|February 26, 2025
PubMed

Insights

Low-dose decitabine (DEC) combined with olaparib (OLA) shows enhanced antitumor activity in KRAS-mutated pancreatic cancer. This combination targets DNA damage response pathways, offering a potential new treatment for pancreatic ductal adenocarcinoma.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Pancreatic ductal adenocarcinoma (PDAC) exhibits poor response to chemotherapy, necessitating novel biomarkers for personalized treatment strategies.
  • Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are prevalent in PDAC, and tumors dependent on KRAS (dKRAS) present a therapeutic vulnerability.
  • Decitabine (DEC), a hypomethylating agent, shows sensitivity in dKRAS-PDAC cells but has limitations in solid tumors due to side effects.

Purpose of the Study:

  • To investigate the efficacy of combining low-dose decitabine (DEC) with poly (ADP-ribose) polymerase (PARP) inhibitor olaparib (OLA) in dKRAS-PDAC.
  • To elucidate the underlying DNA damage response (DDR) mechanisms activated by the DEC+OLA combination.
  • To evaluate the effectiveness of this combination in various genetic contexts, including BRCA1/2 status and homologous recombination (HR) proficiency.

Main Methods:

  • Treatment of dKRAS-PDAC models with low-dose DEC and OLA.
  • Assessment of antitumor activity and DNA damage response pathways (ATR/ATM).
  • Evaluation of the role of PARP1-mediated repair in treatment efficacy.
  • Analysis of efficacy in tumors with different KRAS dependency, BRCA1/2 mutations, and HR proficiency.

Main Results:

  • The combination of DEC and OLA significantly enhanced antitumor activity in dKRAS-PDAC.
  • DEC induced DNA damage and activated the ATR/ATM-mediated DDR, with PARP1-mediated repair being crucial.
  • OLA synergized with DEC, improving efficacy particularly in BRCA1/2-wild-type and HR-proficient tumors, and notably in dKRAS-PDAC with BRCA2 mutations, suppressing metastasis.

Conclusions:

  • The combination of low-dose DEC and OLA demonstrates potent antitumor effects in dKRAS-PDAC by targeting DNA damage and repair pathways.
  • This therapeutic strategy shows promise even in tumors with proficient homologous recombination and wild-type BRCA1/2.
  • The DEC+OLA combination warrants further clinical investigation for the treatment of pancreatic ductal adenocarcinoma.
Keywords:
CancerPharmacology

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