Phosphatidylinositol-3 kinase inhibitors enhance the anti-leukemia effect of STI571

Klejman, Agata; Rushen, Lori; Morrione, Andrea; Słupianek, Artur; Skórski, Tomasz

doi:10.1038/sj.onc.1205724

Cited by 134 publications

(77 citation statements)

References 92 publications

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“…In contrast, the non-a isoforms of class I PI3K, p110b, p110g and p110d, have an inherent oncogenic activity as wild-type proteins. This observation is in accord with evidence showing that p110d and p110g are involved in the development and progression of malignancies, such as acute and chronic myeloid leukemia (Skorski et al, 1995(Skorski et al, , 1997Klejman et al, 2002;Min et al, 2003;Kharas et al, 2004;Kubota et al, 2004;Grandage et al, 2005;Sujobert et al, 2005;Hickey and Cotter, 2006;Martelli et al, 2006;Billottet et al). Recent structural studies have advanced our understanding of the mechanisms that mediate the gain of function in cancer-specific mutations of p110a (Miled et al, 2007).…”

Section: Discussionsupporting

confidence: 85%

Oncogenic signaling of class I PI3K isoforms

et al. 2007

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The catalytic subunits of class I PI3Ks comprise four isoforms: p110a, p110b, p110d and p110c. Cancer-specific gain-of-function mutations in p110a have been identified in various malignancies. Cancer-specific mutations in the non-a isoforms of class I PI3K have not yet been identified, however overexpression of either wild-type p110b, p110c or p110d is sufficient to induce cellular transformation in chicken embryo fibroblasts. The mechanism whereby these non-a isoforms of class I mediate oncogenic signals is unknown. Here we show that potently transforming class I isoforms signal via Akt/mTOR, inhibit GSK3b and cause degradation of FoxO1. A functional Erk pathway is required for p110c and p110b transformation but not for transformation by p110d or the H1047R mutant of p110a. Transformation and signaling by p110c and p110b are sensitive to loss of interaction with Ras, which acts as a membrane anchor. Mutations in the C2 domain of p110d reduce transformation, most likely by interfering with membrane association. Several small molecule inhibitors potently and specifically inhibit the oncogenic signaling and transformation of each of the class I PI3K, and, when used in combination with MEK inhibitors, can additively reduce the transformation induced by p110b and p110c.

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Section: Discussionsupporting

confidence: 85%

Oncogenic signaling of class I PI3K isoforms

et al. 2007

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“…This suggests that, as compared with IL-3, BCR/ABL is more dependent on Rap1-mediated signaling pathways, which agrees with the idea that cancer cells depend on a few highly activated signaling pathways and are particularly sensitive to inhibition of these pathways (Klein et al, 2005). This also agrees with previous observations that PI3K inhibitors exerted a selective antileukemic effect in CML cells while sparing normal counterparts and synergized with imatinib to inhibit growth of human CML cells (Skorski et al, 1995;Klejman et al, 2002;Marley et al, 2004). Thus, the present study proposes that the Rap1-mediated signaling pathways may represent attractive targets for novel therapies for BCR/ABLexpressing leukemias.…”

Section: Rap1 Activation By Bcr/abl and Il-3supporting

confidence: 90%

BCR/ABL and IL-3 activate Rap1 to stimulate the B-Raf/MEK/Erk and Akt signaling pathways and to regulate proliferation, apoptosis, and adhesion

et al. 2006

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“…Identifying kinase inhibitors that target the ATP-binding site of a kinase can be fraught with specificity problems because all kinases and many other molecules possess ATP-binding sites. This was perhaps best observed with STI-571 (Gleevec, imatinib mesylate, Novartis Pharma, Basel, Switzerland), a competitive inhibitor of the ATP-binding site of many kinases (Klejman et al, 2002). The wide clinical application of STI-571 is partially due to its ability to inhibit many kinases, including bcrabl, platelet-derived growth factor receptors, and c-Kit (Heinrich et al, 2000;McGary et al, 2002;von Bubnoff et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

RETRACTED ARTICLE: The Akt inhibitor KP372-1 suppresses Akt activity and cell proliferation and induces apoptosis in thyroid cancer cells

et al. 2005

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The phosphatidylinositol 3 0 kinase (PI3K)/phosphatase and tensin homologue deleted on chromosome ten/Akt pathway, which is a critical regulator of cell proliferation and survival, is mutated or activated in a wide variety of cancers. Akt appears to be a key central node in this pathway and thus is an attractive target for targeted molecular therapy. We demonstrated that Akt is highly phosphorylated in thyroid cancer cell lines and human thyroid cancer specimens, and hypothesised that KP372-1, an Akt inhibitor, would block signalling through the PI3K pathway and inhibit cell proliferation while inducing apoptosis of thyroid cancer cells. KP372-1 blocked signalling downstream of Akt in thyroid tumour cells, leading to inhibition of cell proliferation and increased apoptosis. As thyroid cancer consistently expresses phosphorylated Akt and KP372-1 effectively blocks Akt signalling, further preclinical evaluation of this compound for treatment of thyroid cancer is warranted.

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Phosphatidylinositol-3 kinase inhibitors enhance the anti-leukemia effect of STI571

Cited by 134 publications

References 92 publications

Oncogenic signaling of class I PI3K isoforms

Oncogenic signaling of class I PI3K isoforms

BCR/ABL and IL-3 activate Rap1 to stimulate the B-Raf/MEK/Erk and Akt signaling pathways and to regulate proliferation, apoptosis, and adhesion

RETRACTED ARTICLE: The Akt inhibitor KP372-1 suppresses Akt activity and cell proliferation and induces apoptosis in thyroid cancer cells

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