Discovery of NVP-BYL719 a potent and selective phosphatidylinositol-3 kinase alpha inhibitor selected for clinical evaluation

Furet, Pascal; Guagnano, Vito; Fairhurst, Robin A.; Imbach‐Weese, Patricia; Bruce, Ian; Knapp, Mark; Fritsch, Christine; Blasco, Francesca; Blanz, Joachim; Aichholz, Reiner; Hamon, Jacques; Fabbro, Doriano; Caravatti, Giorgio

doi:10.1016/j.bmcl.2013.05.007

Cited by 350 publications

(282 citation statements)

References 29 publications

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“…Contrary to current dogma, these observations suggest that PTEN can also act as an oncogene as well as a tumor suppressor. Lastly, we demonstrate that cells expressing this mutant allele are sensitive to treatment with PI3K inhibitors that are currently undergoing clinical testing (25,26). These results add another layer to the findings of PTEN lossof-function and dominant-negative mutations implicated with tumorigenesis (cf.…”

Section: Significancesupporting

confidence: 58%

Discovery and functional characterization of a neomorphic PTEN mutation

Costa

Leitner

Sos

et al. 2015

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

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Although a variety of genetic alterations have been found across cancer types, the identification and functional characterization of candidate driver genetic lesions in an individual patient and their translation into clinically actionable strategies remain major hurdles. Here, we use whole genome sequencing of a prostate cancer tumor, computational analyses, and experimental validation to identify and predict novel oncogenic activity arising from a point mutation in the phosphatase and tensin homolog (PTEN) tumor suppressor protein.We demonstrate that this mutation (p.A126G) produces an enzymatic gain-of-function in PTEN, shifting its function from a phosphoinositide (PI) 3-phosphatase to a phosphoinositide (PI) 5-phosphatase. Using cellular assays, we demonstrate that this gain-of-function activity shifts cellular phosphoinositide levels, hyperactivates the PI3K/ Akt cell proliferation pathway, and exhibits increased cell migration beyond canonical PTEN loss-of-function mutants. These findings suggest that mutationally modified PTEN can actively contribute to welldefined hallmarks of cancer. Lastly, we demonstrate that these effects can be substantially mitigated through chemical PI3K inhibitors. These results demonstrate a new dysfunction paradigm for PTEN cancer biology and suggest a potential framework for the translation of genomic data into actionable clinical strategies for targeted patient therapy.functional genomics | PTEN | tumor suppressor

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Section: Significancesupporting

confidence: 58%

Discovery and functional characterization of a neomorphic PTEN mutation

Costa

Leitner

Sos

et al. 2015

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

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“…Because p110 isoform-selective inhibitors are available, and some of them are entering clinical trials (33), we sought to verify the isoform dependence shown in the genetic model using pharmacological inhibitors. For this study we used BYL719, a p110α-selective inhibitor currently in clinical trials for cancer patients (34), and KIN193, a p110β-selective inhibitor that effectively reduces PI3K signaling in some PTEN-deficient cancer cells (23).…”

Section: Pharmacological Inhibition Of P110α Effectively Blocks Tumormentioning

confidence: 99%

PI3K isoform dependence of PTEN-deficient tumors can be altered by the genetic context

Schmit

Utermark

Zhang

et al. 2014

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

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There has been increasing interest in the use of isoform-selective inhibitors of phosphatidylinositide-3-kinase (PI3K) in cancer therapy. Using conditional deletion of the p110 catalytic isoforms of PI3K to predict sensitivity of cancer types to such inhibitors, we and others have demonstrated that tumors deficient of the phosphatase and tensin homolog (PTEN) are often dependent on the p110β isoform of PI3K. Because human cancers usually arise due to multiple genetic events, determining whether other genetic alterations might alter the p110 isoform requirements of PTEN-null tumors becomes a critical question. To investigate further the roles of p110 isoforms in PTEN-deficient tumors, we used a mouse model of ovarian endometrioid adenocarcinoma driven by concomitant activation of the rat sarcoma protein Kras, which is known to activate p110α, and loss of PTEN. In this model, ablation of p110β had no effect on tumor growth, whereas p110α ablation blocked tumor formation. Because ablation of PTEN alone is often p110β dependent, we wondered if the same held true in the ovary. Because PTEN loss alone in the ovary did not result in tumor formation, we tested PI3K isoform dependence in ovarian surface epithelium (OSE) cells deficient in both PTEN and p53. These cells were indeed p110β dependent, whereas OSEs expressing activated Kras with or without PTEN loss were p110α dependent. Furthermore, isoform-selective inhibitors showed a similar pattern of the isoform dependence in established Kras G12D /PTEN-deficient tumors. Taken together, our data suggest that, whereas in some tissues PTEN-null tumors appear to inherently depend on p110β, the p110 isoform reliance of PTEN-deficient tumors may be altered by concurrent mutations that activate p110α.ovarian cancer | PI3K inhibitors | genetically engineered mouse model

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“…The drug was introduced in the simulation model after deriving the mechanism of action (MOA) of each drug based on published research (Adams et al, 1999;Piperdi et al, 2011;Furet et al, 2013;Young et al, 2013) and validation of the mechanism across retrospective studies. The directly inhibited/activated primary (and secondary as well as tertiary in some cases) targets of the compound reported in the experimental literature were modulated with experimentally-determined kinetic constants.…”

Section: In Silico Simulation Of Biological Effectmentioning

confidence: 99%

PI3KCA plays a major role in multiple myeloma and its inhibition with BYL719 decreases proliferation, synergizes with other therapies and overcomes stroma-induced resistance

Azab

Vali²,

Abraham

et al. 2014

Br J Haematol

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SummaryThe phosphatidylinositide 3-kinase (PI3K) pathway is activated and correlated with drug resistance in multiple myeloma (MM). In the present study we investigated the role of PI3KCA (PI3K-a) in the progression and drug resistance in MM. We showed that the gene expression of PI3KCA isoform was higher in MM compared to normal subjects. BYL719, a novel and specific PI3KCA inhibitor inhibited the survival of primary MM cells and cell lines but not normal peripheral blood mononuclear cells. BYL719 induced the apoptosis of MM cells and inhibited their cell cycle by causing G1 arrest. BYL719 inhibited PI3K signalling, decreased proliferation and cells cycle signalling, and induced apoptosis signalling in MM cells. Finally, BYL719 synergized with bortezomib and carfilzomib, and overcame drug resistance induced by bone marrow stroma. These results were confirmed using in silico simulation of MM cell lines, BYL719 and bortezomib, and showed similar trends in survival, proliferation, apoptosis, cell signalling and synergy with drugs. In conclusion, PI3KCA plays a major role in proliferation and drug resistance of MM cells, the effects of which were inhibited with BYL719. These results provide a preclinical basis for a future clinical trial of BYL719 in MM as a single agent or in combination with other drugs.

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Discovery of NVP-BYL719 a potent and selective phosphatidylinositol-3 kinase alpha inhibitor selected for clinical evaluation

Cited by 350 publications

References 29 publications

Discovery and functional characterization of a neomorphic PTEN mutation

Discovery and functional characterization of a neomorphic PTEN mutation

PI3K isoform dependence of PTEN-deficient tumors can be altered by the genetic context

PI3KCA plays a major role in multiple myeloma and its inhibition with BYL719 decreases proliferation, synergizes with other therapies and overcomes stroma-induced resistance

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