Phosphatidylinositol 3-Kinase, Growth Disorders, and Cancer

Goncalves, Marcus D.; Hopkins, Benjamin D.; Cantley, Lewis C.

doi:10.1056/nejmra1704560

Cited by 219 publications

(193 citation statements)

References 80 publications

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“…Class IA PI3Ks are regulated through a complex network of inter and intra-protein interactions with its regulatory domains. Perturbations of the interaction between the p110 catalytic subunits and regulatory subunits through activating mutations is causative of multiple human diseases, including cancer (Fruman et al, 2017;Samuels et al, 2004), primary immunodeficiencies (Angulo et al, 2013;Dornan and Burke, 2018;Lucas et al, 2016), and developmental disorders (Goncalves and Cantley, 2018;Lindhurst et al, 2012;Rivière et al, 2012;Venot et al, 2018). Mutations mediate activation of PI3K activity through disruption of key inhibitory interfaces or through induction of allosteric conformational changes that mimic natural activation mechanisms of class IA PI3Ks (Burke et al, 2012;Dornan et al, 2017;Takeda et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Defining how oncogenic and developmental mutations ofPIK3R1alter the regulation of class IA phosphoinositide 3-kinases

Dornan

Stariha

Rathinaswamy

et al. 2019

Preprint

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The class IA PI3Ks are key signalling enzymes composed of a heterodimer of a p110 catalytic subunit and a p85 regulatory subunit, with PI3K mutations being causative of multiple human diseases including cancer, primary immunodeficiencies, and developmental disorders.Mutations in the p85α regulatory subunit encoded by PIK3R1 can both activate PI3K through oncogenic truncations in the iSH2 domain, or inhibit PI3K through developmental disorder mutations in the cSH2 domain. Using a combined biochemical and hydrogen deuterium exchange mass spectrometry approach we have defined the molecular basis for how these mutations activate both the p110α/p110δ catalytic subunits. We find that the oncogenic Q572* truncation of PIK3R1 disrupts all inhibitory inputs, with p110α being hyper-activated compared to p110δ. In addition, we find that the R649W mutation in the cSH2 of PIK3R1 decreases sensitivity to activation by receptor tyrosine kinases. This work reveals novel insight into isoform specific regulation of p110s by p85α.Keywords: PI3K, p110, p85, phosphoinositide 3-kinase, PI3K-Akt, HDX-MS, hydrogen exchange, phosphoinositides, PIK3CA, PIK3R1Defining the p85 mechanisms that mediate the inhibition and activation of PI3K Highlights-An oncogenic variant of p85α, Q572*, leads to hyper-activation of p110α compared to p110δ -HDX-MS revealed that Q572* leads to disruption of all inhibitory interfaces in p110α -A SHORT syndrome mutation in p85α leads to decreased sensitivity to RTKs for p110α/δ Defining the p85 mechanisms that mediate the inhibition and activation of PI3K

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Section: Discussionmentioning

confidence: 99%

Defining how oncogenic and developmental mutations ofPIK3R1alter the regulation of class IA phosphoinositide 3-kinases

Dornan

Stariha

Rathinaswamy

et al. 2019

Preprint

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“…[1] Importantly, PI3K product formation leads to the subsequent activation of serine-threonine kinase AKT and mTOR. [3] Many natural-product PI3K inhibitors, such as wortmannin, have side effects and poor metabolic stability. [3] Many natural-product PI3K inhibitors, such as wortmannin, have side effects and poor metabolic stability.…”

Section: Introductionmentioning

confidence: 99%

“…[2] Since the PI3K pathway is frequently deregulated in tumors, it is an attractive target for drug development as both a therapeutic and as an adjunct to improve current treatments. [3] Many natural-product PI3K inhibitors, such as wortmannin, have side effects and poor metabolic stability. [4] Side effects result from inhibition of normal homeostatic functions of PI3K, such as metabolic, inflammatory, and memory functions.…”

Section: Introductionmentioning

confidence: 99%

Oxidative Cyclization‐Induced Activation of a Phosphoinositide 3‐Kinase Inhibitor for Enhanced Selectivity of Cancer Chemotherapeutics

et al. 2019

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In this work, we designed a prodrug that reacts with cellular oxidative equivalents leading to ether cleavage and cyclization to release an active phosphatidylinositol 3-kinase (PI3K) inhibitor. We show that the compound reduces affinity for PI3KA relative to the PI3K inhibitor, is slow to intercellularly oxidize, and is resistant to liver microsomes. We observed modest activity in untreated acute myeloid leukemia cells and 14-fold selectivity relative to non-cancerous cells. The cellular activity of the compound can be modulated by the addition of antiox-idants or oxidants, indicating the compound activity is sensitive to cellular reactive oxygen species (ROS) state. Co-treatment with cytosine arabinoside or doxorubicin was used to activate the compound inside cells. We observed strong synergistic activity specifically in acute myeloid leukemia (AML) cancer cells with an increase in selective anticancer activity of up to 90-fold. Thus, these new self-cyclizing compounds can be used to increase the selectivity of anticancer agents.

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“…Alpelisib was approved by the United States Food and Drug Administration (FDA) in May 2019 for the treatment of hormone receptor‐positive, human epidermal growth factor receptor 2 (HER2)‐negative, PIK3CA mutant advanced or metastatic breast cancer. In the SOLAR‐1 study [1], alpelisib combined with fulvestrant was shown to prolong progression‐free survival compared with placebo. PI3K signalling is important for many cellular functions such as cell proliferation, and also mediates the metabolic actions of insulin [2]. Insulin binds to the insulin receptor, and activates the PI3K signalling cascade via a series of phosphorylation steps, resulting in glucose uptake in skeletal muscle and adipocytes by glucose transporter 4.…”

Section: Answersmentioning

confidence: 99%

“…Insulin binds to the insulin receptor, and activates the PI3K signalling cascade via a series of phosphorylation steps, resulting in glucose uptake in skeletal muscle and adipocytes by glucose transporter 4. In the liver, insulin signalling via PI3K stimulates glycogen synthesis and inhibits gluconeogenesis [2]. There are four isoforms of PI3K (α, β, γ, δ).…”

Section: Answersmentioning

confidence: 99%

Novel breast cancer treatment leads to hyperglycaemia

et al. 2020

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A 66-year-old woman with pre-diabetes and hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer was started on fulvestrant, and referred to endocrinology prior to initiation of alpelisib. Because of anticipated possible hyperglycaemia, and the woman's reluctance to start fingerstick glucose monitoring, a continuous glucose monitor (CGM) was prescribed for safety. CGM data revealed the rapid onset of hyperglycaemia over the first 2 weeks of alpelisib treatment with nocturnal hyperglycaemia (Fig. 1). Hyperglycaemia occurred in the first 6 h after each dose was administered, and after 2 weeks average daily glucose levels were three times higher than baseline.Questions 1. What is alpelisib? Why does alpelisib cause hyperglycaemia?3. How is alpelisib-induced hyperglycaemia treated? FIGURE 1 Two-week continuous glucose monitoring data from woman with breast cancer the day after initiating alpelisib. The woman took alpelisib daily at 6pm. Daily average (Avg) glucose readings are shown.ª 2020 Diabetes UK

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Phosphatidylinositol 3-Kinase, Growth Disorders, and Cancer

Cited by 219 publications

References 80 publications

Defining how oncogenic and developmental mutations ofPIK3R1alter the regulation of class IA phosphoinositide 3-kinases

Defining how oncogenic and developmental mutations ofPIK3R1alter the regulation of class IA phosphoinositide 3-kinases

Oxidative Cyclization‐Induced Activation of a Phosphoinositide 3‐Kinase Inhibitor for Enhanced Selectivity of Cancer Chemotherapeutics

Novel breast cancer treatment leads to hyperglycaemia

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