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Proc Natl Acad Sci U S A. 2016 Jul 26;113(30):E4338-47. doi: 10.1073/pnas.1522223113. Epub 2016 Jul 8.

Phosphoinositide 3-kinase inhibitors induce DNA damage through nucleoside depletion.

Author information

1
Division of Hematology-Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;
2
Department of Medicine, Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065;
3
Longwood Small Animal Imaging Facility, Beth Israel Deaconess Medical Center, Boston, MA 02215;
4
Division of Signal Transduction, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;
5
Department of Surgery, Yale University School of Medicine, New Haven, CT 06520;
6
Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea;
7
Division of Interdisciplinary Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215;
8
Center for Drug Discovery, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30332.
9
Department of Medicine, Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065; lcantley@med.cornell.edu gwulf@bidmc.harvard.edu.
10
Division of Hematology-Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215; lcantley@med.cornell.edu gwulf@bidmc.harvard.edu.

Abstract

We previously reported that combining a phosphoinositide 3-kinase (PI3K) inhibitor with a poly-ADP Rib polymerase (PARP)-inhibitor enhanced DNA damage and cell death in breast cancers that have genetic aberrations in BRCA1 and TP53. Here, we show that enhanced DNA damage induced by PI3K inhibitors in this mutational background is a consequence of impaired production of nucleotides needed for DNA synthesis and DNA repair. Inhibition of PI3K causes a reduction in all four nucleotide triphosphates, whereas inhibition of the protein kinase AKT is less effective than inhibition of PI3K in suppressing nucleotide synthesis and inducing DNA damage. Carbon flux studies reveal that PI3K inhibition disproportionately affects the nonoxidative pentose phosphate pathway that delivers Rib-5-phosphate required for base ribosylation. In vivo in a mouse model of BRCA1-linked triple-negative breast cancer (K14-Cre BRCA1(f/f)p53(f/f)), the PI3K inhibitor BKM120 led to a precipitous drop in DNA synthesis within 8 h of drug treatment, whereas DNA synthesis in normal tissues was less affected. In this mouse model, combined PI3K and PARP inhibition was superior to either agent alone to induce durable remissions of established tumors.

KEYWORDS:

DNA damage; Parp-inhibition; breast cancer; phosphoinositide 3-kinase; tumor metabolism

PMID:
27402769
PMCID:
PMC4968752
DOI:
10.1073/pnas.1522223113
[Indexed for MEDLINE]
Free PMC Article

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