Loss of INPP4B causes a DNA repair defect through loss of BRCA1, ATM and ATR and can be targeted with PARP inhibitor treatment

Ip, Laura R. H.; Poulogiannis, George; Viciano, Felipe Cia; Sasaki, Junko; Kofuji, Satoshi; Spanswick, Victoria J.; Hochhauser, Daniel; Hartley, John A.; Sasaki, Takehiko; Gewinner, Christina

doi:10.18632/oncotarget.3307

Cited by 27 publications

(27 citation statements)

References 48 publications

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“…Aside from their role in regulating the homeostasis of phospho-inositides, PTEN and INPP4B may have independent roles in DNA damage repair. A role for PTEN in the maintenance of genomic stability was identified (8); more recently, INPP4B was found to directly interact with BRCA1 and the serine/threonine protein kinase ATR, and its loss destabilizes these DNA damage repair complexes, effectively sensitizing INPP4B-deficient cells to poly-ADP Rib polymerase (PARP) inhibition (9).…”

mentioning

confidence: 99%

Phosphoinositide 3-kinase inhibitors induce DNA damage through nucleoside depletion

Juvekar

Yadegarynia

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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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), 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. T riple-negative breast cancers, including BRCA1-linked breast cancers, frequently show activation of the PI3K pathway as a result of overexpression of epidermal growth factor receptor (EGFR) (1, 2) or insulin-like growth factor 1 receptor (IGFR) (3), and inhibition of the EGFR (1, 2, 4) and/or the PI3K/Nrf2 axis (5) prevents cancers arising from BRCA1 mutant mammary epithelial cells (MECs). In addition, activating mutations of PIK3CA, or loss of the inhibitory lipid phosphatases PTEN (phosphatase and tensin homolog) and INPP4B (inositol polyphosphate 4-phosphatase type II) (6, 7), suggest that the PI3K pathway is contributing to tumor growth and survival. Aside from their role in regulating the homeostasis of phospho-inositides, PTEN and INPP4B may have independent roles in DNA damage repair. A role for PTEN in the maintenance of genomic stability was identified (8); more recently, INPP4B was found to directly interact with BRCA1 and the serine/threonine protein kinase ATR, and its loss destabilizes these DNA damage repair complexes, effectively sensitizing INPP4B-deficient cells to poly-ADP Rib polymerase (PARP) inhibition (9).Despite the high incidence of predisposing lesions in the PI3K pathway, limited clinical activity has been observed with PI3K inhibitors as single-agent treatment in endocrine-resistant breast cancer, which may reflect bypass of PI3K-dependent mitogenic signaling by alternative signaling pathways such as the MAPK pathway. Therefore, concurrent inhibition of parallel and compensatory signaling networks to overcome resistance to PI3K inhibition is being investigated in clinical studies. This approach, however, carries the risk of overlapping toxicities of the targeted agents without sufficient efficacy because tumor cells may have greater plasticity for redundant signaling than normal tissues.Mul...

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confidence: 99%

Phosphoinositide 3-kinase inhibitors induce DNA damage through nucleoside depletion

Juvekar

Yadegarynia

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…ATM, ATR, BRCA1, and RAD51 are important components of HR repair pathway and play a vital role in HR repair [28,29]. And it has been reported that INPP4B loss results in DNA repair deficiency via loss of BRCA1, ATM, and ATR in ovarian cancer cells [24]. In primary AML, higher BRCA1 mRNA level, decreased PARP1 mRNA, and p-H2AX expression can be the markers to predict resistance to response [30].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, a growing number of reports have suggested that upregulation of DNA damage response (DDR) genes can provide AML cells with escaping from mechanisms to the DDR anticancer barrier and induce chemotherapy resistance [23]. Given that INPP4B loss is reported to be concomitant loss of ATM, ATR, and BRCA1 in ovarian tumors [24], and its role of resistance to genotoxic treatment in AML, we therefore speculate that INPP4B-mediated resistance to genotoxic treatment is correlated with DNA repair pathway in AML.…”

Section: Introductionmentioning

confidence: 99%

INPP4B-mediated DNA repair pathway confers resistance to chemotherapy in acute myeloid leukemia

Wang

et al. 2016

Tumor Biol.

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INPP4B has been recently shown to be a poor prognostic marker and confer chemo- or radio-resistance in AML cells, whereas, the underlying mechanisms remain unclear. Herein, we aimed to explore the possible mechanisms mediated the resistance to chemotherapy in AML. We found that INPP4B-mediated resistance to genotoxic drug, cytarabine, was accompanied by lower p-H2AX accumulation in KG-1 cells, and INPP4B knockdown evidently sensitized KG-1 cells to cytarabine, meanwhile, p-H2AX expression was increased dramatically. Then, we observed that INPP4B knockdown inhibited the loss of p-H2AX expression after cytarabine removal in INPP4B-silenced KG-1 cells, whereas, in control KG-1 cells, the expression of p-H2AX was reduced in a time-dependent manner. Next, INPP4B knockdown can significantly downregulate ATM expression and subsequently inhibit the activation of ATM downstream targets of p-ATM, p-BRCA1, p-ATR, and p-RAD51. Furthermore, nuclear localization of p65 was inhibited after INPP4B knockdown, and reactivation of p65 can rescue the INPP4B knockdown-induced inhibition of ATM, p-ATM, p-BRCA1, p-ATR, and p-RAD51. Finally, INPP4B expression was positively correlated with ATM expression in AML cells, both INPP4B knockdown and KU55933 can significantly sensitize primary myeloid leukemic cells to cytarabine treatment.Collectively, these data suggest that enhanced ATM-dependent DNA repair is involved in resistance to chemotherapy in INPP4B AML, which could be mediated by p65 nuclear translocation, combination chemotherapy with INPP4B or DNA repair pathway inhibition represents a promising strategy in INPP4B AML.

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“…INPP4B loss resulted in significantly increased PARP sensitivity in vitro models, as well as in vivo xenograft models. INPP4B forms a protein complex with ATR and BRCA1, in GST pull-down and 293T overexpression assays, and INPP4B loss affected BRCA1, ATM and ATR protein stability resulting in the observed DNA repair defect [67]. Thus, a defect in the repair of DNA damage due to a loss of a phosphatase belonging to the PI3K pathway has been demonstrated to be associated with the loss of BRCA1, ATM, and ATR and was targeted by PARP inhibitor.…”

Section: Pi3k-akt-mtor Pathway Inhibition In the Context Of Ddr: Parpmentioning

confidence: 99%

“…On the flip side of it, overexpression of INPP4B which encodes the inositol polyphosphate 4-phosphatase type II, one of the other phosphatase involved in phosphatidylinositol signaling pathways (removes the phosphate group at position 4 of the inositol ring from inositol 3,4-bisphosphate) has been shown to enhance the antitumor efficacy of PARP inhibitor AG014699 in MDA-MB-231 TNBC cells [146]. Loss of INPP4B has been shown to cause a DNA repair defect through loss of BRCA1, ATM and ATR and can be targeted with PARP inhibitor treatment [67].…”

Section: Parp Inhibitors As Chemo/radiopotentiating Agents: Tnbc and mentioning

confidence: 99%

PI3K-AKT-mTOR Pathway Cooperates with the DNA Damage Repair Pathway: Carcinogenesis in Triple-Negative Breast Cancers and Beyond

Carlson

Leyland‐Jones

et al. 2016

Cancer Drug Discovery and Development

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Loss of INPP4B causes a DNA repair defect through loss of BRCA1, ATM and ATR and can be targeted with PARP inhibitor treatment

Cited by 27 publications

References 48 publications

Phosphoinositide 3-kinase inhibitors induce DNA damage through nucleoside depletion

Phosphoinositide 3-kinase inhibitors induce DNA damage through nucleoside depletion

INPP4B-mediated DNA repair pathway confers resistance to chemotherapy in acute myeloid leukemia

PI3K-AKT-mTOR Pathway Cooperates with the DNA Damage Repair Pathway: Carcinogenesis in Triple-Negative Breast Cancers and Beyond

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