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Phosphoinositide 3-kinase inhibitors induce DNA damage through nucleoside depletion

Ashish Juvekar1, Hai Hu1, Sina Yadegarynia1

  • 1Division of Hematology-Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;

Proceedings of the National Academy of Sciences of the United States of America
|July 13, 2016
PubMed

Insights

Combining PI3K inhibitors with PARP inhibitors enhances DNA damage and cell death in BRCA1/TP53-mutated breast cancers by impairing nucleotide synthesis. This combination therapy shows superior tumor remission in preclinical models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Previous research indicated that combining phosphoinositide 3-kinase (PI3K) inhibitors with poly-ADP Rib polymerase (PARP)-inhibitors enhanced DNA damage and cell death in breast cancers with BRCA1 and TP53 genetic aberrations.
  • The precise mechanism by which PI3K inhibition contributes to enhanced DNA damage in this context remained to be fully elucidated.

Purpose of the Study:

  • To investigate the underlying mechanisms of enhanced DNA damage induced by PI3K inhibitors in BRCA1/TP53-mutated breast cancer.
  • To compare the effects of PI3K inhibition versus AKT inhibition on nucleotide synthesis and DNA damage.
  • To evaluate the in vivo efficacy of combined PI3K and PARP inhibition in a preclinical model of BRCA1-linked triple-negative breast cancer.

Main Methods:

  • Utilized PI3K inhibitors and assessed their impact on nucleotide triphosphate levels and DNA synthesis.
  • Employed carbon flux studies to investigate the effects of PI3K inhibition on metabolic pathways, specifically the pentose phosphate pathway.
  • Conducted in vivo studies using a genetically engineered mouse model (K14-Cre BRCA1(f/f)p53(f/f)) of triple-negative breast cancer, evaluating the effects of PI3K inhibitor BKM120 on DNA synthesis and tumor response to combined PI3K and PARP inhibition.

Main Results:

  • PI3K inhibition, unlike AKT inhibition, significantly reduced all four nucleotide triphosphates, impairing DNA synthesis and repair.
  • PI3K inhibition disproportionately affected the nonoxidative pentose phosphate pathway, crucial for nucleotide production.
  • In vivo, BKM120 rapidly decreased DNA synthesis in tumors with BRCA1/TP53 mutations, with minimal impact on normal tissues.
  • Combined PI3K and PARP inhibition demonstrated superior efficacy in achieving durable tumor remission compared to single-agent treatment in the mouse model.

Conclusions:

  • Enhanced DNA damage from PI3K inhibitors in BRCA1/TP53-mutated breast cancer is due to impaired nucleotide production, primarily affecting the pentose phosphate pathway.
  • PI3K inhibition is a key driver of synthetic lethality when combined with PARP inhibitors in this specific cancer subtype.
  • Combined PI3K and PARP inhibition represents a promising therapeutic strategy for BRCA1-linked triple-negative breast cancer.
Keywords:
DNA damageParp-inhibitionbreast cancerphosphoinositide 3-kinasetumor metabolism

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