PI3K inhibitors in inflammation, autoimmunity and cancer

Stark, Anne-Katrien; Sriskantharajah, Srividya; Hessel, Edith M.; Okkenhaug, Klaus

doi:10.1016/j.coph.2015.05.017

Cited by 249 publications

(194 citation statements)

References 80 publications

(107 reference statements)

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“…The PI3K–protein kinase B (PI3K–Akt) pathway regulates the size, survival, angiogenesis, and inflammation of cardiomyocytes 32. PI3K signalling can promote proinflammatory cytokine production by activating nuclear factor‐κB (NFκB) downstream of AKT and can mediate IL‐6 expression, which, in our study, was down‐regulated by microcurrent 33. TGF‐β plays a central role in the induction of fibrosis by stimulation of the Smad system, which in turn increases the expression of collagen types I, III, and VI and accelerates the production of extracellular matrix proteins 31.…”

Section: Discussionmentioning

confidence: 61%

Bioelectrical signals improve cardiac function and modify gene expression of extracellular matrix components

et al. 2017

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AimsBeyond the influence of stimulating devices on cardiac excitation, their use in treating patients with heart failure has positive effects on the myocardium at the molecular level. Electrical signals can induce a wide spectrum of effects in living tissue. Therefore, we sought to determine whether applying electrical microcurrent directly to failing hearts leads to functional improvement.Methods and resultsSixteen male spontaneously hypertensive rats (SHRs) with heart failure underwent application of a patch electrode to the left ventricular epicardium and placement of a subcutaneous counter electrode. The electrode delivered a 0.35 μA microcurrent to nine of the SHRs for 45 ± 3 days; the other seven SHRs were used as controls. At baseline and before the SHRs were humanely put to death, we measured the left ventricular ejection fraction (LVEF) and the thickness of the LV posterior wall during systole and diastole (LVPWs/d). We used quantitative PCR to determine extracellular matrix parameters [collagen I–III, matrix metalloproteinase (MMP)‐2, MMP‐9, tissue inhibitor of metalloproteinases 3 (TIMP3), TIMP4, connexins (Cxs) 40/43/45, transforming growth factor (TGF)‐β, and interleukin (IL)‐6].Among SHRs undergoing microcurrent application, LVEF normalized (mean decrease, 22.8%; P = 0.009), and LVPWs decreased (mean, 35.3%; P = 0.001). Compared with the control group, the SHRs receiving microcurrent exhibited a mean decrease in the gene expression of collagen I (10.6%, P = 0.003), TIMP3 (18.5%, P = 0.005), Cx43 (14.3%, P = 0.003), Cx45 (12.7%, P = 0.020), TGF‐β (13.0%, P = 0.005), and IL‐6 (53.7%, P = 0.000). Microcurrent application induced no changes in the expression of collagen III, MMP‐2, MMP‐9, TIMP4, or Cx40.ConclusionsApplying microcurrent to the LV epicardium of SHRs leads to statistically significant functional improvement and alterations in the levels of inflammatory and extracellular matrix components.

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Section: Discussionmentioning

confidence: 61%

Bioelectrical signals improve cardiac function and modify gene expression of extracellular matrix components

et al. 2017

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“…Importantly, class IA PI3K isoforms (PI3Ka, b, d) are adapted to regulation by receptors signal through protein tyrosin kinases, whereas class IB PI3K (PI3Kg) is adapted to regulation by GPCRs via direct binding to Gbg subunits. [26][27][28][29] Tim-3 expression, in response to certain cytokines, has been reported to be induced by activation of the PI3K pathway. 26 We previously showed that pS6 is decreased in TIL after PD-1 stimulation, 30 potentially linking PD-1 to the PI3K-Akt-mTOR pathway.…”

Section: Tim-3 Upregulation Upon Pd-1 Blockade Requires Activation Ofmentioning

confidence: 99%

“…[26][27][28][29] Tim-3 expression, in response to certain cytokines, has been reported to be induced by activation of the PI3K pathway. 26 We previously showed that pS6 is decreased in TIL after PD-1 stimulation, 30 potentially linking PD-1 to the PI3K-Akt-mTOR pathway. Since TCR/CD28 co-stimulation leads to PI3K/Akt activation, and PD-1 ligation causes inhibition of TCR proximal signaling through SHP-2 27 , leading to decreased PI3K activity, we hypothesized that Tim-3 upregulation after PD-1 blockade might be caused by increased PI3K activity due to de-repression by PD-1 blockade.…”

Section: Tim-3 Upregulation Upon Pd-1 Blockade Requires Activation Ofmentioning

confidence: 99%

Adaptive resistance to anti-PD1 therapy by Tim-3 upregulation is mediated by the PI3K-Akt pathway in head and neck cancer

et al. 2016

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Programmed Death 1 (PD-1) and T cell Ig and mucin domain-3 protein (Tim-3) are immune checkpoint receptors that are expressed on tumor-infiltrating lymphocytes (TIL) in tumor-bearing mice and humans. As anti-PD-1 single agent response rates are only <20% in head and neck squamous cell carcinoma (HNSCC) patients, it is important to understand how multiple inhibitory checkpoint receptors maintain suppressed cellular immunity. One such receptor, Tim-3, activates downstream proliferative pathways through Akt/S6, and is highly expressed in dysfunctional TIL. We observed that PD-1 and Tim-3 coexpression was associated with a more exhausted phenotype, with the highest PD-1 levels on TIL coexpressing Tim-3. Dampened Akt/S6 phosphorylation in these PD-1 C Tim-3 C TIL, when the PD-1 pathway was ligated, suggested that signaling cross-talk could lead to escape through Tim-3 expression. Indeed, PD-1 blockade of human HNSCC TIL led to further Tim-3 upregulation, supporting a circuit of compensatory signaling and potentially permitting escape from anti-PD-1 blockade in the tumor microenvironment. Also, in a murine HNC tumor model that is partially responsive to anti-PD-1 therapy, Tim-3 was upregulated in TIL from persistently growing tumors. Significant antitumor activity was observed after sequential addition of anti-Tim-3 mAb to overcome adaptive resistance to anti-PD-1 mAb. This increased Tim-3-mediated escape of exhausted TIL from PD-1 inhibition that was mediated by phospho-inositol-3 kinase (PI3K)/Akt complex downstream of TCR signaling but not cytokine-mediated pathways. Taken together, we conclude that during PD-1 blockade, TIL upregulate Tim-3 in a PI3K/Aktdependent manner, providing further support for dual targeting of these molecules for more effective cancer immunotherapy.

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“…Hence, manipulation of the PI3K pathway represents an interesting approach for treatment of a number of different pathological conditions such as cancer, where inhibitors of class IA PI3K with varying isoform selectivity profiles have already been established as treatment options for different indications. 1 In the immune system, the PI3K delta isoform plays a central role in both innate and adaptive immune cell functions. Taking advantage of the strong dependency of B cells on functional PI3Kδ, 2 the oral PI3Kδ inhibitor Idelalisib has been successfully developed as a novel treatment for different types of B-cell malignancies.…”

mentioning

confidence: 99%

Discovery of a Potent, Selective, and Orally Available PI3Kδ Inhibitor for the Treatment of Inflammatory Diseases

Erra

Taltavull

Gréco

et al. 2016

ACS Med. Chem. Lett.

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The delta isoform of the phosphatidylinositol 3-kinase (PI3Kδ) has been shown to have an essential role in specific immune cell functions and thus represents a potential therapeutic target for autoimmune and inflammatory diseases. Herein, the optimization of a series of pyrrolotriazinones as potent and selective PI3Kδ inhibitors is described. The main challenge of the optimization process was to identify an orally available compound with a good pharmacokinetic profile in preclinical species that predicted a suitable dosing regimen in humans. Structure−activity relationships and structure−property relationships are discussed. This medicinal chemistry exercise led to the identification of LAS191954 as a candidate for clinical development.

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PI3K inhibitors in inflammation, autoimmunity and cancer

Cited by 249 publications

References 80 publications

Bioelectrical signals improve cardiac function and modify gene expression of extracellular matrix components

Bioelectrical signals improve cardiac function and modify gene expression of extracellular matrix components

Adaptive resistance to anti-PD1 therapy by Tim-3 upregulation is mediated by the PI3K-Akt pathway in head and neck cancer

Discovery of a Potent, Selective, and Orally Available PI3Kδ Inhibitor for the Treatment of Inflammatory Diseases

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