title: Phosphoinositide 3-kinase inhibitors induce DNA damage through nucleoside depletion.
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.
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;
authors.forename: Ashish
authors.initials: A
authors.lastname: Juvekar
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;
authors.forename: Hai
authors.initials: H
authors.lastname: Hu
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;
authors.forename: Sina
authors.initials: S
authors.lastname: Yadegarynia
authors.affiliation: Department of Medicine, Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065;
authors.forename: Costas A
authors.initials: CA
authors.lastname: Lyssiotis
authors.affiliation: Longwood Small Animal Imaging Facility, Beth Israel Deaconess Medical Center, Boston, MA 02215;
authors.forename: Soumya
authors.initials: S
authors.lastname: Ullas
authors.affiliation: Division of Signal Transduction, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;
authors.forename: Evan C
authors.initials: EC
authors.lastname: Lien
authors.affiliation: Department of Surgery, Yale University School of Medicine, New Haven, CT 06520;
authors.forename: Gary
authors.initials: G
authors.lastname: Bellinger
authors.affiliation: Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea;
authors.forename: Jaekyoung
authors.initials: J
authors.lastname: Son
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;
authors.forename: Rosanna C
authors.initials: RC
authors.lastname: Hok
authors.affiliation: Division of Interdisciplinary Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215;
authors.forename: Pankaj
authors.initials: P
authors.lastname: Seth
authors.affiliation: Center for Drug Discovery, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30332.
authors.forename: Michele B
authors.initials: MB
authors.lastname: Daly
authors.affiliation: Center for Drug Discovery, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30332.
authors.forename: Baek
authors.initials: B
authors.lastname: Kim
authors.affiliation: Division of Hematology-Oncology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;
authors.forename: Ralph
authors.initials: R
authors.lastname: Scully
authors.affiliation: Division of Signal Transduction, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;
authors.forename: John M
authors.initials: JM
authors.lastname: Asara
authors.affiliation: Department of Medicine, Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10065; lcantley@med.cornell.edu gwulf@bidmc.harvard.edu.
authors.forename: Lewis C
authors.initials: LC
authors.lastname: Cantley
authors.affiliation: 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.
authors.forename: Gerburg M
authors.initials: GM
authors.lastname: Wulf
mesh_terms: D000631:Aminopyridines / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology; D009705:Nucleosides / Q000378:metabolism*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism
chemical_list: D000631:Aminopyridines; D004273:DNA, Neoplasm; D009025:Morpholines; C571178:NVP-BKM120; D009705:Nucleosides; D000081082:Phosphoinositide-3 Kinase Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D058539:Phosphatidylinositol 3-Kinase
keywords: DNA damage; Parp-inhibition; breast cancer; phosphoinositide 3-kinase; tumor metabolism