Drugging the PI3 kinome

Workman, Paul; Clarke, Paul A.; Guillard, Sandrine; Raynaud, Florence I.

doi:10.1038/nbt0706-794

Cited by 65 publications

(60 citation statements)

References 11 publications

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“…The importance of aberrant PI3K signalling in cancer has been recognised for many years (Hennessy et al, 2005;Woodgett, 2005;Vogt et al, 2006;Workman et al, 2006). Apart from promoting cell growth, several signalling pathways diverge downstream from activated PKB/Akt that suppresses apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Activity of a novel, dual PI3-kinase/mTor inhibitor NVP-BEZ235 against primary human pancreatic cancers grown as orthotopic xenografts

et al. 2009

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The phosphatidylinositol-3-kinase (PI3K)/Akt signalling pathway is frequently deregulated in pancreatic cancers, and is believed to be an important determinant of their biological aggression and drug resistance. NVP-BEZ235 is a novel, dual class I PI3K/mammalian target of rapamycin (mTor) inhibitor undergoing phase I human clinical trials. To simulate clinical testing, the effects of NVP-BEZ235 were studied in five early passage primary pancreatic cancer xenografts, grown orthotopically. These tumours showed activated PKB/Akt, and increased levels of at least one of the receptor tyrosine kinases that are commonly activated in pancreatic cancers. Pharmacodynamic effects were measured following acute single doses, and anticancer effects were determined in separate groups following chronic drug exposure. Acute oral dosing with NVP-BEZ235 strongly suppressed the phosphorylation of PKB/Akt, followed by recovery over 24 h. There was also inhibition of Ser235/236 S6 ribosomal protein and Thr37/46 4E-BP1, consistent with the effects of NVP-BEZ235 as a dual PI3K/mTor inhibitor. Chronic dosing with 45 mg kg À1 of NVP-BEZ235 was well tolerated, and produced significant tumour growth inhibition in three models. These results predict that agents targeting the PI3K/Akt/mTor pathway might have anticancer activity in pancreatic cancer patients, and support the testing of combination studies involving chemotherapy or other molecular targeted agents.

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Section: Discussionmentioning

confidence: 99%

Activity of a novel, dual PI3-kinase/mTor inhibitor NVP-BEZ235 against primary human pancreatic cancers grown as orthotopic xenografts

et al. 2009

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“…Taking into account that in addition to Mek, PI3 also contributes to the activation of Erk-1/2, at least after the first nonreinforced contextual presentation (Chen et al, 2005), it remains to be determined whether these pathways converge on Erk as the main mediator, or Erk and Akt synergistically act on downstream processes associated with fear reduction. Thus, some of the numerous PI3/Akt substrates belonging to the Wnt, NF kappaB or other protein kinase pathways (Workman et al, 2006) may act in concert with Erk-1/2 to enable extinction.…”

Section: Discussionmentioning

confidence: 99%

Hippocampal Mek/Erk signaling mediates extinction of contextual freezing behavior

Fischer

Radulović

Schrick

et al. 2007

Neurobiology of Learning and Memory

103

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Fear memories elicit multiple behavioral responses, encompassing avoidance or behavioral inhibition in response to threatening contexts. Context-specific freezing, reflecting fear-induced behavioral inhibition, has been proposed as one of the main risks factors for the development of anxiety disorders. We attempted to define the key hippocampal mediators of extinction in a mouse model of context-dependent freezing. Nine-week-old male C57BL/6J mice were trained and tested for contextual fear conditioning and extinction. Freezing behavior scored by unbiased sampling, was used as an index of fear. Proteomic, immunoblot and immunohistochemical approaches were employed to identify, verify and analyze the alterations of the hippocampal extracellular signalregulated kinases 1 and 2 (Erk-1/2). Targeted pharmacological inhibition of the Erk-1/2 activating kinase, the mitogen activated and extracellular signal-regulated kinase (Mek), served to establish the role of Mek/Erk signaling in extinction. When compared to acquisition, extinction of contextual freezing triggered a rapid activation of Erk-1/2 showing a distinctive time-course, nuclear localization and subcellular isoform distribution. These differences suggested that the upstream regulation and downstream effects of this pathway might be specific for each process. Dorsohippocampal injections of the Mek inhibitors U0126 (0.5 μg/site) and PD98059 (1.5 μg/site) immediately after the nonreinforced trials prevented Erk-1/2 activation and significantly impaired extinction. This effect was dissociable from potential actions on memory retrieval or reconsolidation. On the basis of these findings, we propose that hippocampal Mek/Erk signaling might serve as one of the key mediators of contextual fear extinction.

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“…Although the family of PI3Ks is an attractive and promising target for small-molecule inhibitors in cancer therapy, toxicity associated with pan-selective inhibition of PI3Ks and Akt has been a major hurdle preventing the translation of this approach to patients. 32 In addition, several subunits and isoforms of PI3Ks and Akt exist, making the design of appropriate drugs increasingly difficult. In contrast to PI3Ks and Akt, only a single isoform of PDK1 has been reported in humans, which has a high specificity for phosphorylation and activation of all three Akt isoforms.…”

Section: Discussionmentioning

confidence: 99%

Effects of small molecule inhibitors of PI3K/Akt/mTOR signaling on neuroblastoma growth in vitro and in vivo

Segerström

Baryawno

Sveinbjørnsson

et al. 2011

Intl Journal of Cancer

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Activation of the PI3K/Akt signaling pathway is correlated with poor prognosis in neuroblastoma, the most common and deadly extracranial tumor of childhood. In this study, we show that the small-molecule inhibitors of phosphoinositidedependent protein kinase-1 (PDK1) OSU03012 and the dual class I PI3K/mTOR inhibitor PI103 have profound effects on neuroblastoma survival in vitro and in vivo. Both OSU03012 and PI103 inhibited neuroblastoma growth in vitro. In treated cells, OSU03012 induced apoptosis and an S phase cell cycle arrest, whereas only minor apoptosis was detected in PI103 treated cells together with a G1 arrest. Both OSU03012 and PI103 downregulated phosphorylation of Akt and inhibited the downstream targets glycogen synthase kinase-3b (GSK3b) and p70 S6 kinase-1 (S6K1), as well as downregulated the expression of cyclin D1 and Mycn protein. Neuroblastoma cells expressing high levels of Mycn were more sensitive to OSU03012 or PI103 compared with cells expressing low Mycn levels. Both compounds significantly inhibited the growth of established, subcutaneous MYCN-amplified neuroblastoma xenografts in nude NMRI nu/nu mice. These results suggest that inhibition of the PI3K/Akt signaling pathway represent a clinical relevant target for the treatment of patients with high-risk MYCN-amplified neuroblastoma.Neuroblastomas are peripheral nervous system tumors that originate in the neural crest and are most commonly found in the adrenal medulla or along the sympathetic chain. 1 These tumors show heterogeneous biological and clinical features, in which a subset is prone to regress through spontaneous apoptosis with little or no therapy while another subset differentiates over time to benign ganglioneuromas. However, the majority of neuroblastomas are malignant with metastatic spread that is difficult to cure with current treatment modalities.2 Amplification of the MYCN gene, which occurs in 40-50% of the high-risk neuroblastoma cases, remains the major key predictor of poor outcome and is associated with advanced-stage disease, rapid tumor progression and low survival.3 Advanced-stage tumors and those with MYCN gene amplification typically show emergence of treatment resistance and new treatment alternatives for these patients are highly warranted.Abnormal activation of the PI3K/Akt signaling pathway is a common event in human cancers and has been validated through epidemiological and experimental studies as being essential for several human tumors, including neuroblastoma.4-6 PI3K is a family of lipid kinases, heterodimeric proteins composed of one catalytic and one regulatory subunit. In the class IA PI3Ks, there are currently three isoforms of the catalytic (p110a, b, and d) and five of the regulatory (p50a, p55a, p85a, p85b, and p55c) subunits, where p50a and p55a are splice variants of p85a. PI3Ks functions as signal transducers downstream of cell-surface receptors, such as receptor tyrosine kinases. Activated PI3Ks phosphorylate the lipid phosphatidyl-inositol 4,5-biphosphate (PIP2) to generate phosphatidyl-...

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Drugging the PI3 kinome

Cited by 65 publications

References 11 publications

Activity of a novel, dual PI3-kinase/mTor inhibitor NVP-BEZ235 against primary human pancreatic cancers grown as orthotopic xenografts

Activity of a novel, dual PI3-kinase/mTor inhibitor NVP-BEZ235 against primary human pancreatic cancers grown as orthotopic xenografts

Hippocampal Mek/Erk signaling mediates extinction of contextual freezing behavior

Effects of small molecule inhibitors of PI3K/Akt/mTOR signaling on neuroblastoma growth in vitro and in vivo

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