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Modulation of pancreatic cancer cell sensitivity to FOLFIRINOX through microRNA-mediated regulation of DNA damage

Pietro Carotenuto1,2, Francesco Amato3, Andrea Lampis4

  • 1Division of Cancer Therapeutics, The Institute of Cancer Research, London, UK.

Nature Communications
|November 19, 2021
PubMed

Insights

MicroRNAs (MIR) can modulate chemotherapy sensitivity in pancreatic ductal adenocarcinoma (PDAC). Targeting MIR1307 enhances FOLFIRINOX efficacy by increasing apoptosis and DNA damage, suggesting MIR1307 as a predictive biomarker.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy.
  • FOLFIRINOX (Fluorouracil, Oxaliplatin, Irinotecan) is a standard chemotherapy for PDAC.
  • MicroRNAs (MIR) are implicated in cancer progression and drug resistance.

Purpose of the Study:

  • To investigate the role of microRNAs (MIR) in modulating chemotherapy sensitivity in PDAC.
  • To identify potential microRNA (MIR) biomarkers for FOLFIRINOX response.
  • To explore MIR1307 as a modulator of chemosensitivity.

Main Methods:

  • Screening of microRNA (MIR) inhibitors in PDAC cell lines (Capan1, MiaPaCa2).
  • Validation of MIR1307 targeting using knock-out (MIR1307KO) and re-expression models.
  • Assessment of apoptosis and DNA damage.
  • RNA cross-linking immunoprecipitation (CLIP) to identify mRNA targets.
  • In vivo validation in a mouse model.
  • Analysis of circulating MIR1307 in PDAC patients receiving FOLFIRINOX.

Main Results:

  • MicroRNA (MIR) inhibitors enhanced chemosensitivity in PDAC cells.
  • MIR1307 inhibition increased chemotherapy-induced apoptosis and DNA damage.
  • MIR1307 was found to bind to CLIC5 mRNA.
  • MIR1307 disruption improved outcomes in an in vivo PDAC model.
  • Circulating MIR1307 levels correlated with clinical outcomes in PDAC patients.

Conclusions:

  • MIR1307 acts as a negative regulator of chemosensitivity in pancreatic ductal adenocarcinoma (PDAC).
  • Targeting MIR1307 enhances FOLFIRINOX efficacy through increased apoptosis and DNA damage.
  • Circulating MIR1307 shows potential as a predictive biomarker for FOLFIRINOX treatment response in PDAC patients.

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