bims-pideca Biomed News
on Class IA PI3K signalling in development and cancer
Issue of 2024–09–15
fifteen papers selected by
Ralitsa Radostinova Madsen, MRC-PPU
  1. FoxO transcription factors actuate the formative pluripotency specific gene expression programme.
  2. ContactBlot: Microfluidic Control and Measurement of the Cell-Cell Contact State to Assess Contact-Inhibited ERK Signaling.
  3. SeqVerify: An accessible analysis tool for cell line genomic integrity, contamination, and gene editing outcomes.
  4. Combined inhibition of CDK4/6 and AKT is highly effective against the luminal androgen receptor (LAR) subtype of triple negative breast cancer.
  5. Light-gated integrator for highlighting kinase activity in living cells.
  6. Clinical Neurologic Features and Evaluation of PTEN Hamartoma Tumor Syndrome: A Systematic Review.
  7. New insights into the regulation and roles of phosphatidylinositol 3,4-bisphosphate.
  8. Increased RNA and protein degradation is required for counteracting transcriptional burden and proteotoxic stress in human aneuploid cells.
  9. Multifocal, multiphenotypic tumours arising from an MTOR mutation acquired in early embryogenesis.
  10. SHANK3 depletion leads to ERK signalling overdose and cell death in KRAS-mutant cancers.
  11. Novel phosphatidylinositol flippases contribute to phosphoinositide homeostasis in the plasma membrane.
  12. Endothelial metabolic control of insulin sensitivity through resident macrophages.
  13. Live Cell Painting: image-based profiling in live cells using Acridine Orange.
  14. Laws of thought in living cells.
  15. A highly selective PI3Kδ inhibitor BGB-10188 shows superior preclinical anti-tumor activities and decreased on-target side effects on colon.
  1. Nat Commun. 2024 Sep 09. 15(1): 7879
    FoxO transcription factors actuate the formative pluripotency specific gene expression programme.
    Laura Santini, Saskia Kowald, Luis Miguel Cerron-Alvan, Michelle Huth, Anna Philina Fabing, Giovanni Sestini, Nicolas Rivron, Martin Leeb.
      Naïve pluripotency is sustained by a self-reinforcing gene regulatory network (GRN) comprising core and naïve pluripotency-specific transcription factors (TFs). Upon exiting naïve pluripotency, embryonic stem cells (ESCs) transition through a formative post-implantation-like pluripotent state, where they acquire competence for lineage choice. However, the mechanisms underlying disengagement from the naïve GRN and initiation of the formative GRN are unclear. Here, we demonstrate that phosphorylated AKT acts as a gatekeeper that prevents nuclear localisation of FoxO TFs in naïve ESCs. PTEN-mediated reduction of AKT activity upon exit from naïve pluripotency allows nuclear entry of FoxO TFs, enforcing a cell fate transition by binding and activating formative pluripotency-specific enhancers. Indeed, FoxO TFs are necessary and sufficient for the activation of the formative pluripotency-specific GRN. Our work uncovers a pivotal role for FoxO TFs in establishing formative post-implantation pluripotency, a critical early embryonic cell fate transition.
    DOI:  https://doi.org/10.1038/s41467-024-51794-9
  2. Anal Chem. 2024 Sep 10.
    ContactBlot: Microfluidic Control and Measurement of the Cell-Cell Contact State to Assess Contact-Inhibited ERK Signaling.
    Yizhe Zhang, Isao Naguro, Hiroki Ryuno, Amy E Herr.
      Extracellular signal-regulated kinase (ERK) signaling is essential to regulated cell behaviors, including cell proliferation, differentiation, and apoptosis. The influence of cell-cell contacts on ERK signaling is central to epithelial cells, yet few studies have sought to understand the same in cancer cells, particularly with single-cell resolution. To acquire same-cell measurements of both phenotypic (cell-contact state) and targeted-protein (ERK phosphorylation) profiles, we prepend high-content, whole-cell imaging prior to end-point cellular-resolution Western blot analyses for each of hundreds of individual HeLa cancer cells cultured on that same chip, which we call contactBlot. By indexing the phosphorylation level of ERK in each cell or cell cluster to the imaged cell-contact state, we compare the ERK signaling between isolated and in-contact cells. We observe attenuated (∼2×) ERK signaling in HeLa cells that are in-contact versus isolated. Attenuation is sustained when the HeLa cells are challenged with hyperosmotic stress. Our findings show the impact of cell-cell contacts on ERK activation with isolated and in-contact cells while introducing a multi-omics tool for control and scrutiny of cell-cell interactions.
    DOI:  https://doi.org/10.1021/acs.analchem.4c02936
  3. Stem Cell Reports. 2024 Aug 26. pii: S2213-6711(24)00242-X. [Epub ahead of print]
    SeqVerify: An accessible analysis tool for cell line genomic integrity, contamination, and gene editing outcomes.
    Merrick Pierson Smela, Valerio Pepe, Steven Lubbe, Evangelos Kiskinis, George M Church.
      Over the last decade, advances in genome editing and pluripotent stem cell (PSC) culture have let researchers generate edited PSC lines to study a wide variety of biological questions. However, abnormalities in cell lines such as aneuploidy, mutations, on-target and off-target editing errors, and microbial contamination can arise during PSC culture or due to undesired editing outcomes. The ongoing decline of next-generation sequencing prices has made whole-genome sequencing (WGS) a promising option for detecting these abnormalities. However, this approach has been held back by a lack of easily usable data analysis software. Here, we present SeqVerify, a computational pipeline designed to take raw WGS data and a list of intended genome edits, and verify that the edits are present and that there are no abnormalities. We anticipate that SeqVerify will be a useful tool for researchers generating edited PSCs, and more broadly, for cell line quality control in general.
    Keywords:  SeqVerify; aneuploidy; genome editing; microbial contamination; pluripotent stem cell; quality control; single-nucleotide polymorphisms; software; stem cell; whole-genome sequencing
    DOI:  https://doi.org/10.1016/j.stemcr.2024.08.004
  4. Cancer Lett. 2024 Sep 05. pii: S0304-3835(24)00614-1. [Epub ahead of print] 217219
    Combined inhibition of CDK4/6 and AKT is highly effective against the luminal androgen receptor (LAR) subtype of triple negative breast cancer.
    María Rosario Chica-Parrado, Gun Min Kim, Yasuaki Uemoto, Fabiana Napolitano, Chang-Ching Lin, Dan Ye, Emmanuel Bikorimana, Yisheng Fang, Kyung-Min Lee, Saurabh Mendiratta, Ariella B Hanker, Carlos L Arteaga.
      Luminal Androgen Receptor (LAR) triple-negative breast cancers (TNBC) express androgen receptors (AR), exhibit high frequency of PIK3CA mutations and intact RB. Herein, we investigated combined blockade of the CDK4/6 and PI3K signaling with palbociclib, alpelisib, and capivasertib, which inhibit CDK4/6, PI3Kα, and AKT1-3, respectively. The combination of palbociclib/capivasertib, but not palbociclib/alpelisib, synergistically inhibited proliferation of MDA-MB-453 and MFM-223 LAR cells [synergy score 7.34 (p=5.81x10-11) and 4.78 (p=0.012), respectively]. The AR antagonist enzalutamide was inactive against MDA-MB-453, MFM-223, and CAL148 cells and did not enhance the efficacy of either combination. Palbociclib/capivasertib inhibited growth of LAR patient-derived xenografts more potently than palbociclib/alpelisib. Treatment of LAR cells with palbociclib suppressed phosphorylated-RB and resulted in adaptive phosphorylation/activation of S473 pAKT and AKT substrates GSK3β, PRAS40, and FoxO3a. Capivasertib blocked palbociclib-induced phosphorylation of AKT substrates more potently than alpelisib. Treatment with PI3Kβ inhibitors did not block phosphorylation of AKT substrates, suggesting that PI3Kβ did not mediate the adaptive response to CDK4/6 inhibition. Phosphokinase arrays of MDA-MB-453 cells treated with palbociclib showed time-dependent upregulation of PDGFRβ, GSK3β, STAT3, and STAT6. RNA silencing of PDGFRβ in palbociclib-treated MDA-MB-453 and MFM-223 cells blocked the upregulation of S473 pAKT, suggesting that the adaptive response to CDK4/6 blockade involves PDGFRβ signaling. Finally, treatment with palbociclib and the PDGFR inhibitor CP637451 arrested growth of MDA-MB-453 and MFM-223 cells to the same degree as palbociclib/capivasertib. These findings support testing the combination of CDK4/6 and AKT inhibitors in patients with LAR TNBC, and further investigation of PDGFR antagonists in this breast cancer subtype.
    Keywords:  CDK4/6 blockade; PDGFRβ; PI3K/AKT inhibitors; targeted therapy; triple negative breast cancer
    DOI:  https://doi.org/10.1016/j.canlet.2024.217219
  5. Nat Commun. 2024 Sep 06. 15(1): 7804
    Light-gated integrator for highlighting kinase activity in living cells.
    Wei Lin, Abhishek Phatarphekar, Yanghao Zhong, Longwei Liu, Hyung-Bae Kwon, William H Gerwick, Yingxiao Wang, Sohum Mehta, Jin Zhang.
      Protein kinases are key signaling nodes that regulate fundamental biological and disease processes. Illuminating kinase signaling from multiple angles can provide deeper insights into disease mechanisms and improve therapeutic targeting. While fluorescent biosensors are powerful tools for visualizing live-cell kinase activity dynamics in real time, new molecular tools are needed that enable recording of transient signaling activities for post hoc analysis and targeted manipulation. Here, we develop a light-gated kinase activity coupled transcriptional integrator (KINACT) that converts dynamic kinase signals into "permanent" fluorescent marks. KINACT enables robust monitoring of kinase activity across scales, accurately recording subcellular PKA activity, highlighting PKA activity distribution in 3D cultures, and identifying PKA activators and inhibitors in high-throughput screens. We further leverage the ability of KINACT to drive signaling effector expression to allow feedback manipulation of the balance of GαsR201C-induced PKA and ERK activation and dissect the mechanisms of oncogenic G protein signaling.
    DOI:  https://doi.org/10.1038/s41467-024-51270-4
  6. Neurology. 2024 Oct 08. 103(7): e209844
    Clinical Neurologic Features and Evaluation of PTEN Hamartoma Tumor Syndrome: A Systematic Review.
    Andrew Dhawan, Sarah Baitamouni, Darren Liu, Charis Eng.
       BACKGROUND AND OBJECTIVES: PTEN hamartoma tumor syndrome (PHTS) is a well-recognized hereditary tumor syndrome and is now also recognized as a common cause of monogenic autism spectrum disorder. There is a vast spectrum of phenotypic variability across individuals with PHTS, and in addition to neurodevelopmental challenges, patients with PHTS may experience a wide variety of neurologic challenges, many of which have only recently been described. Thus, this systematic review aimed to summarize the breadth of the current knowledge of neurologic conditions in individuals with PHTS.
    METHODS: We conducted a systematic review using the MEDLINE and EMBASE databases until January 2023. We included studies that reported neurologic signs, symptoms, and diagnoses in patients with a diagnosis of PHTS. Two independent reviewers extracted data (neurologic diagnoses and patient details) from each study. Case reports, case series, prospective studies, and therapeutic trials were included. We assessed the quality of evidence using the appropriate tool from the JBI, depending on study design.
    RESULTS: One thousand nine hundred ninety-six articles were screened, and 90 articles met the inclusion criteria. The majority of the included studies were case reports (49/90, 54%) or small case series (31/90, 34%). Epilepsy secondary to cerebral malformations, neurologic deficits from spinal or cranial arteriovenous malformations, and rare tumors such as dysplastic cerebellar gangliocytoma are among the more severe neurologic features reported across patients with PHTS. One interventional randomized control trial examining neurocognitive endpoints was identified and did not meet its efficacy endpoint.
    DISCUSSION: Our systematic review defines a broad scope of neurologic comorbidities occurring in individuals with PHTS. Neurologic findings can be categorized by age at onset in individuals with PTHS. Our study highlights the need for additional clinical trial endpoints, informed by the neurologic challenges faced by individuals with PHTS.
    DOI:  https://doi.org/10.1212/WNL.0000000000209844
  7. J Biochem. 2024 Sep 13. pii: mvae063. [Epub ahead of print]
    New insights into the regulation and roles of phosphatidylinositol 3,4-bisphosphate.
    Junya Hasegawa.
      Phosphoinositides (PIPs) are phospholipids and components of the cellular membrane. In mammals, seven phosphorylated derivatives of PIPs have been identified. Among them, phosphatidylinositol 3,4-bisphosphate [PI(3,4)P2] is produced by lipid phosphatases (e.g., SHIP2) or by lipid kinases PI3KC2α and PI3KC2β. Although PI(3,4)P2 is undetectable in normal mouse or human tissues and common cell lines, it appears in a mouse prostate cancer model and in cells exposed to oxidative stress, indicating that PI(3,4)P2 is involved in the pathogenesis of some diseases. Here, I summarize recent findings on the cellular roles and pathophysiological significance of PI(3,4)P2.
    Keywords:  4-bisphosphate; Cancer; Membrane ruffle; Membrane trafficking; Phosphatidylinositol 3; Phosphoinositides
    DOI:  https://doi.org/10.1093/jb/mvae063
  8. Cancer Discov. 2024 Sep 09.
    Increased RNA and protein degradation is required for counteracting transcriptional burden and proteotoxic stress in human aneuploid cells.
    Marica Rosaria Ippolito, Johanna Zerbib, Yonatan Eliezer, Eli Reuveni, Sonia Vigano, Giuseppina De Feudis, Eldad D Shulman, Anouk Savir Kadmon, Rachel Slutsky, Tiangen Chang, Emma M Campagnolo, Silvia Taglietti, Simone Scorzoni, Sara Gianotti, Sara Martin, Julia Muenzner, Michael Mulleder, Nir Rozenblum, Carmela Rubolino, Tal Ben-Yishay, Kathrin Laue, Yael Cohen-Sharir, Ilaria Vigorito, Francesco Nicassio, Eytan Ruppin, Markus Ralser, Francisca Vazquez, Stefano Santaguida, Uri Ben-David.
      Aneuploidy results in a stoichiometric imbalance of protein complexes that jeopardizes cellular fitness. Aneuploid cells thus need to compensate for the imbalanced DNA levels by regulating their RNA and protein levels, but the underlying molecular mechanisms remain unknown. Here, we dissected multiple diploid vs. aneuploid cell models. We found that aneuploid cells cope with transcriptional burden by increasing several RNA degradation pathways, and are consequently more sensitive to the perturbation of RNA degradation. At the protein level, aneuploid cells mitigate proteotoxic stress by reducing protein translation and increasing protein degradation, rendering them more sensitive to proteasome inhibition. These findings were recapitulated across hundreds of human cancer cell lines and primary tumors, and aneuploidy levels were significantly associated with the response of multiple myeloma patients to proteasome inhibitors. Aneuploid cells are therefore preferentially dependent on several key nodes along the gene expression process, creating clinically-actionable vulnerabilities in aneuploid cells.
    DOI:  https://doi.org/10.1158/2159-8290.CD-23-0309
  9. Oncogene. 2024 Sep 13.
    Multifocal, multiphenotypic tumours arising from an MTOR mutation acquired in early embryogenesis.
    Clarissa N Pacyna, Madhanagopal Anandapadamanaban, Kevin W Loudon, Iain M Hay, Olga Perisic, Ruoyan Li, Matthew Byrne, Laura Allen, Kirsty Roberts, Yvette Hooks, Anne Y Warren, Grant D Stewart, Menna R Clatworthy, Sarah A Teichmann, Sam Behjati, Peter J Campbell, Roger L Williams, Thomas J Mitchell.
      Embryogenesis is a vulnerable time. Mutations in developmental cells can result in the wide dissemination of cells predisposed to disease within mature organs. We characterised the evolutionary history of four synchronous renal tumours from a 14-year-old girl using whole genome sequencing alongside single cell and bulk transcriptomic sequencing. Phylogenetic reconstruction timed the origin of all tumours to a multipotent embryonic cell committed to the right kidney, around 4 weeks post-conception. Biochemical and structural analysis of their shared MTOR mutation, absent from normal tissues, demonstrates enhanced protein flexibility, enabling a FAT domain hinge to dramatically increase activity of mTORC1 and mTORC2. Developmental mutations, not usually detected in traditional genetic screening, have vital clinical importance in guiding prognosis, targeted treatment, and family screening decisions for paediatric tumours.
    DOI:  https://doi.org/10.1038/s41388-024-03137-7
  10. Nat Commun. 2024 Sep 12. 15(1): 8002
    SHANK3 depletion leads to ERK signalling overdose and cell death in KRAS-mutant cancers.
    Johanna Lilja, Jasmin Kaivola, James R W Conway, Joni Vuorio, Hanna Parkkola, Pekka Roivas, Michal Dibus, Megan R Chastney, Taru Varila, Guillaume Jacquemet, Emilia Peuhu, Emily Wang, Ulla Pentikäinen, Itziar Martinez D Posada, Hellyeh Hamidi, Arafath K Najumudeen, Owen J Sansom, Igor L Barsukov, Daniel Abankwa, Ilpo Vattulainen, Marko Salmi, Johanna Ivaska.
      The KRAS oncogene drives many common and highly fatal malignancies. These include pancreatic, lung, and colorectal cancer, where various activating KRAS mutations have made the development of KRAS inhibitors difficult. Here we identify the scaffold protein SH3 and multiple ankyrin repeat domain 3 (SHANK3) as a RAS interactor that binds active KRAS, including mutant forms, competes with RAF and limits oncogenic KRAS downstream signalling, maintaining mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) activity at an optimal level. SHANK3 depletion breaches this threshold, triggering MAPK/ERK signalling hyperactivation and MAPK/ERK-dependent cell death in KRAS-mutant cancers. Targeting this vulnerability through RNA interference or nanobody-mediated disruption of the SHANK3-KRAS interaction constrains tumour growth in vivo in female mice. Thus, inhibition of SHANK3-KRAS interaction represents an alternative strategy for selective killing of KRAS-mutant cancer cells through excessive signalling.
    DOI:  https://doi.org/10.1038/s41467-024-52326-1
  11. Biochem J. 2024 Sep 18. 481(18): 1187-1202
    Novel phosphatidylinositol flippases contribute to phosphoinositide homeostasis in the plasma membrane.
    Yumeka Muranaka, Ryo Shigetomi, Yugo Iwasaki, Asuka Hamamoto, Kazuhisa Nakayama, Hiroyuki Takatsu, Hye-Won Shin.
      Phosphatidylinositol is a precursor of various phosphoinositides, which play crucial roles in intracellular signaling and membrane dynamics and have impact on diverse aspects of cell physiology. Phosphoinositide synthesis and turnover occur in the cytoplasmic leaflet of the organellar and plasma membranes. P4-ATPases (lipid flippases) are responsible for translocating membrane lipids from the exoplasmic (luminal) to the cytoplasmic leaflet, thereby regulating membrane asymmetry. However, the mechanism underlying phosphatidylinositol translocation across cellular membranes remains elusive. Here, we discovered that the phosphatidylcholine flippases ATP8B1, ATP8B2, and ATP10A can also translocate phosphatidylinositol at the plasma membrane. To explore the function of these phosphatidylinositol flippases, we used cells depleted of CDC50A, a protein necessary for P4-ATPase function and ATP8B1 and ATP8B2, which express in HeLa cells. Upon activation of the Gq-coupled receptor, depletion of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] was accelerated in CDC50A knockout (KO) and ATP8B1/8B2 double KO cells compared with control cells, suggesting a decrease in PtdIns(4,5)P2 levels within the plasma membrane of the KO cells upon stimulation. These findings highlight the important role of P4-ATPases in maintaining phosphoinositide homeostasis and suggest a mechanism for asymmetry of phosphatidylinositol in the cytoplasmic leaflet of the plasma membrane.
    Keywords:  P4-ATPase; flippase; lipid transport; phosphatidylinositol; phosphoinositide
    DOI:  https://doi.org/10.1042/BCJ20240223
  12. Cell Metab. 2024 Sep 08. pii: S1550-4131(24)00335-8. [Epub ahead of print]
    Endothelial metabolic control of insulin sensitivity through resident macrophages.
    Jing Zhang, Kim Anker Sjøberg, Songlin Gong, Tongtong Wang, Fengqi Li, Andrew Kuo, Stephan Durot, Adam Majcher, Raphaela Ardicoglu, Thibaut Desgeorges, Charlotte Greta Mann, Ines Soro Arnáiz, Gillian Fitzgerald, Paola Gilardoni, E Dale Abel, Shigeyuki Kon, Danyvid Olivares-Villagómez, Nicola Zamboni, Christian Wolfrum, Thorsten Hornemann, Raphael Morscher, Nathalie Tisch, Bart Ghesquière, Manfred Kopf, Erik A Richter, Katrien De Bock.
      Endothelial cells (ECs) not only form passive blood conduits but actively contribute to nutrient transport and organ homeostasis. The role of ECs in glucose homeostasis is, however, poorly understood. Here, we show that, in skeletal muscle, endothelial glucose transporter 1 (Glut1/Slc2a1) controls glucose uptake via vascular metabolic control of muscle-resident macrophages without affecting transendothelial glucose transport. Lowering endothelial Glut1 via genetic depletion (Glut1ΔEC) or upon a short-term high-fat diet increased angiocrine osteopontin (OPN/Spp1) secretion. This promoted resident muscle macrophage activation and proliferation, which impaired muscle insulin sensitivity. Consequently, co-deleting Spp1 from ECs prevented macrophage accumulation and improved insulin sensitivity in Glut1ΔEC mice. Mechanistically, Glut1-dependent endothelial glucose metabolic rewiring increased OPN in a serine metabolism-dependent fashion. Our data illustrate how the glycolytic endothelium creates a microenvironment that controls resident muscle macrophage phenotype and function and directly links resident muscle macrophages to the maintenance of muscle glucose homeostasis.
    Keywords:  GLUT1; endothelial cells; endothelial metabolism; inflammation; insulin sensitivity; osteopontin; resident macrophages; serine; skeletal muscle; vasculature
    DOI:  https://doi.org/10.1016/j.cmet.2024.08.008
  13. bioRxiv. 2024 Aug 29. pii: 2024.08.28.610144. [Epub ahead of print]
    Live Cell Painting: image-based profiling in live cells using Acridine Orange.
    Fernanda Garcia-Fossa, Thaís Moraes-Lacerda, Mariana Rodrigues-da-Silva, Barbara Diaz-Rohrer, Shantanu Singh, Anne E Carpenter, Beth A Cimini, Marcelo Bispo de Jesus.
      Image-based profiling has been used to analyze cell health, drug mechanism of action, CRISPR-edited cells, and overall cytotoxicity. Cell Painting is a broadly used image-based assay that uses morphological features to capture how cells respond to treatments. However, this method requires cell fixation for staining, which prevents examining live cells. To address this limitation, here we present Live Cell Painting (LCP), a high-content method based on Acridine orange, a metachromatic dye that labels different organelles and cellular structures. We began by showing that LCP can be applied to follow acidic vesicle redistribution of cells exposed to acidic vesicles inhibitors. Next, we show that LCP can identify subtle changes in cells exposed to silver nanoparticles that are not detected by techniques such as MTT assay. In drug treatments, LCP was helpful in assessing the dose-response relationship and creating profiles that allow clustering of drugs that cause liver injury. Here, we present an affordable and easy-to-use image-based assay capable of assessing overall cell health and showing promise for use in various applications such as assessing drugs and nanoparticles. We envisage the use of Live Cell Painting as an initial screening of overall cell health while providing insights into new biological questions.
    DOI:  https://doi.org/10.1101/2024.08.28.610144
  14. Cell. 2024 Sep 05. pii: S0092-8674(24)00896-1. [Epub ahead of print]187(18): 4830-4832
    Laws of thought in living cells.
    Carlise Sorenson, Katarzyna P Adamala.
      Building biological computers is one of the most intensively pursued goals of modern synthetic biology. The new TriLoS tristate-based logic synthesis platform, published in this issue of Cell, offers a long-awaited solution to scale up the complexity of biocomputing, opening a path to move this field beyond proof-of-principle demonstrations.
    DOI:  https://doi.org/10.1016/j.cell.2024.08.005
  15. Neoplasia. 2024 Sep 10. pii: S1476-5586(24)00095-2. [Epub ahead of print]57 101053
    A highly selective PI3Kδ inhibitor BGB-10188 shows superior preclinical anti-tumor activities and decreased on-target side effects on colon.
    Xiao Yang, Huichen Bai, Xi Yuan, Xiaolong Yang, Ye Liu, Mingming Guo, Nan Hu, Beibei Jiang, Zeqin Lian, Zhilong Ma, Jingyuan Wang, Xuebing Sun, Taichang Zhang, Dan Su, Yue Wu, Jing Li, Fan Wang, Zhiwei Wang, Lai Wang, Xuesong Liu, Xiaomin Song.
      PI3Kδ is a key signal transduction molecule in normal and malignant B cells, as well as in T-regulatory cells, making it a promising target for treatment of hematologic malignancies through both direct killing and anti-tumor immunity regulation. BGB-10188 is a highly selective inhibitor of PI3Kδ, showing more than 3000 folds selectivity over other PI3K isoforms and no significant inhibition across tested kinases. BGB-10188 potently inhibited PI3Kδ with IC50s ranging from 1.7-16 nM through various in vitro assays and showed a long-lasting and strong target inhibition in mouse B cells in vivo. BGB-10188 showed significant antitumor effects in human B cell lymphoma xenograft models as single agent or in combination with the BTK inhibitor zanubrutinib. BGB-10188 showed significant Treg inhibition in blood but not in colon, along with less drug accumulation in colon compared with idelalisib, which is an approved PI3Kdelta inhibitor with high incidence of gastrointestinal side effects in clinic. In summary, BGB-10188 is a novel PI3Kδ inhibitor with high selectivity, potency and improved safety profile shown in preclinical studies, which is showing the potential as a best-in-class PI3Kδ inhibitor.
    Keywords:  B cell malignancy; BGB-10188; Colon distribution; PI3Kδ; Treg inhibition
    DOI:  https://doi.org/10.1016/j.neo.2024.101053
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