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

Date Posted: February 8, 2017

TitlePhosphoinositide 3-kinase inhibitors induce DNA damage through nucleoside depletion.
Publication TypeJournal Article
Year of Publication2016
AuthorsJuvekar A, Hu H, Yadegarynia S, Lyssiotis CA, Ullas S, Lien EC, Bellinger G, Son J, Hok RC, Seth P, Daly MB, Kim B, Scully R, Asara JM, Cantley LC, Wulf GM
JournalProc Natl Acad Sci U S A
Volume113
Issue30
PaginationE4338-47
Date Published2016 Jul 26
ISSN1091-6490
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.

DOI10.1073/pnas.1522223113
Alternate JournalProc. Natl. Acad. Sci. U.S.A.
PubMed ID27402769
PubMed Central IDPMC4968752
Grant ListP30 CA046592 / CA / NCI NIH HHS / United States
R01 CA095175 / CA / NCI NIH HHS / United States
R01 AI049781 / AI / NIAID NIH HHS / United States
R01 GM104198 / GM / NIGMS NIH HHS / United States
P01 CA120964 / CA / NCI NIH HHS / United States
P50 CA168504 / CA / NCI NIH HHS / United States
R01 GM041890 / GM / NIGMS NIH HHS / United States
P30 CA006516 / CA / NCI NIH HHS / United States