Antitumor Efficacy Profile of PKI-402, a Dual Phosphatidylinositol 3-Kinase/Mammalian Target of Rapamycin Inhibitor

Mallon, Robert; Hollander, Irwin; Feldberg, Larry; Lucas, Judy; Soloveva, Veronica; Venkatesan, Aranapakam M.; Dehnhardt, Christoph M.; Santos, Efren Delos; Chen, Zecheng; Santos, Osvaldo Dos; Ayral‐Kaloustian, Semiramis; Gibbons, Jacqueline A.

doi:10.1158/1535-7163.mct-09-0954

Cited by 58 publications

(40 citation statements)

References 22 publications

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“…These molecular insights have stimulated the development of PI3K/TOR-KIs (Table 3). These new PI3K/TORKIs have shown powerful effects in xenograft models of breast cancer (126)(127)(128)(129), pancreatic cancer (130), melanoma (131), multiple myeloma (132), glioma (129,133), RCC (134), and acute myeloid leukemia (AML) (135). Like the TOR-KIs, many dual PI3K/TOR-KIs strongly induce apoptosis (128,129,132,134,135) and/or autophagy (133).…”

Section: Beyond Rapalogs: Molecular Rationale and New Therapeutic Strmentioning

confidence: 99%

Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy

Wander¹,

Hennessy²,

Slingerland³

2011

J. Clin. Invest.

371

363

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Section: Beyond Rapalogs: Molecular Rationale and New Therapeutic Strmentioning

confidence: 99%

Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy

Wander¹,

Hennessy²,

Slingerland³

2011

J. Clin. Invest.

371

363

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“…It was found out that PKI-402 inhibits MDA-MB-361 cell line growth in vitro and in vivo by inhibiting the phosphorylation of Akt at Ser473 and Thr308, as well as by inhibiting the downstream target molecules of Akt phosphorylation. PKI-402 induces apoptosis in MDA-MB-361 cells by a caspase-3 dependent pathway [77] . PKI-587 has a similar in vitro and in vivo profile to PKI-402.…”

Section: Current Progress In Clinical Trialsmentioning

confidence: 99%

PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes

2012

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The PI3K-Akt pathway is a vital regulator of cell proliferation and survival. Alterations in the PIK3CA gene that lead to enhanced PI3K kinase activity have been reported in many human cancer types, including cancers of the colon, breast, brain, liver, stomach and lung. Deregulation of PI3K causes aberrant Akt activity. Therefore targeting this pathway could have implications for cancer treatment. The first generation PI3K-Akt inhibitors were proven to be highly effective with a low IC 50 , but later, they were shown to have toxic side effects and poor pharmacological properties and selectivity. Thus, these inhibitors were only effective in preclinical models. However, derivatives of these first generation inhibitors are much more selective and are quite effective in targeting the PI3K-Akt pathway, either alone or in combination. These second-generation inhibitors are essentially a specific chemical moiety that helps to form a strong hydrogen bond interaction with the PI3K/Akt molecule. The goal of this review is to delineate the current efforts that have been undertaken to inhibit the various components of the PI3K and Akt pathway in different types of cancer both in vitro and in vivo. Our focus here is on these novel therapies and their inhibitory effects that depend upon their chemical nature, as well as their development towards clinical trials.

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“…These cell lines have constitutive activation of the PI3K/ mTOR pathway due to oncogenic KRAS mutations (26). H460 cells additionally possess activating mutations of PIK3CA (26).…”

Section: Bez235 Inhibits Dna-pk and Enhances G 2 -M Growth Arrest Aftmentioning

confidence: 99%

Inhibition of DNA-Dependent Protein Kinase Induces Accelerated Senescence in Irradiated Human Cancer Cells

Azad

Jackson

Cullinane

et al. 2011

Molecular Cancer Research

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DNA-dependent protein kinase (DNA-PK) plays a pivotal role in the repair of DNA double-strand breaks (DSB) and is centrally involved in regulating cellular radiosensitivity. Here, we identify DNA-PK as a key therapeutic target for augmenting accelerated senescence in irradiated human cancer cells. We find that BEZ235, a novel inhibitor of DNA-PK and phosphoinositide 3-kinase (PI3K)/mTOR, abrogates radiation-induced DSB repair resulting in cellular radiosensitization and growth delay of irradiated tumor xenografts. Importantly, radiation enhancement by BEZ235 coincides with a prominent p53-dependent accelerated senescence phenotype characterized by positive b-galactosidase staining, G 2 -M cell-cycle arrest, enlarged and flattened cellular morphology, and increased p21 expression and senescence-associated cytokine secretion. Because this senescence response to BEZ235 is accompanied by unrepaired DNA DSBs, we examined whether selective targeting of DNA-PK also induces accelerated senescence in irradiated cells. Significantly, we show that specific pharmacologic inhibition of DNA-PK, but not PI3K or mTORC1, delays DSB repair leading to accelerated senescence after radiation. We additionally show that PRKDC knockdown using siRNA promotes a striking accelerated senescence phenotype in irradiated cells comparable with that of BEZ235. Thus, in the context of radiation treatment, our data indicate that inhibition of DNA-PK is sufficient for the induction of accelerated senescence. These results validate DNA-PK as an important therapeutic target in irradiated cancer cells and establish accelerated senescence as a novel mechanism of radiosensitization induced by DNA-PK blockade. Mol Cancer Res; 9(12); 1696-707. Ó2011 AACR.

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Antitumor Efficacy Profile of PKI-402, a Dual Phosphatidylinositol 3-Kinase/Mammalian Target of Rapamycin Inhibitor

Cited by 58 publications

References 22 publications

Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy

Next-generation mTOR inhibitors in clinical oncology: how pathway complexity informs therapeutic strategy

PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes

Inhibition of DNA-Dependent Protein Kinase Induces Accelerated Senescence in Irradiated Human Cancer Cells

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