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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.

SUBMITTER: Juvekar A

PROVIDER: S-EPMC4968752 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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

Juvekar Ashish A Hu Hai H Yadegarynia Sina S Lyssiotis Costas A CA Ullas Soumya S Lien Evan C EC Bellinger Gary G Son Jaekyoung J Hok Rosanna C RC Seth Pankaj P Daly Michele B MB Kim Baek B Scully Ralph R Asara John M JM Cantley Lewis C LC Wulf Gerburg M GM

Proceedings of the National Academy of Sciences of the United States of America 20160708 30

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, ...[more]

PMID: 27402769

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

Publications

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

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