Abstract 706: In vivo tumor-associated mutation screen identifies PI3K activation as a mechanism of resistance to PD-1 blockade

2018 ◽  
Author(s):  
Natalie B. Collins ◽  
Brian C. Miller ◽  
Kevin Bi ◽  
Rose Al Abosy ◽  
Kathleen Yates ◽  
...  
Keyword(s):  
Mechanism Of Resistance ◽  
Mutation Screen ◽  
Pi3k Activation

In Vivo Validation Of Trogocytosis In Neuroblastoma – A Potential Mechanism Of Resistance To Anti-GD2 Immunotherapy

2021 ◽  
Author(s):  
Abigail K. Zamora ◽  
Michael J. Zobel ◽  
Jianping Sun ◽  
Michael Sheard ◽  
Robert Seeger ◽  
...  
Keyword(s):  
Potential Mechanism ◽  
Mechanism Of Resistance ◽  
In Vivo Validation

scholarly journals CD2AP links actin to PI3 kinase activity to extend epithelial cell height and constrain cell area

2019 ◽  
Vol 219 (1) ◽  
Author(s):  
Yuou Wang ◽  
William M. Brieher
Keyword(s):  
Actin Polymerization ◽  
Mdck Cells ◽  
Cell Area ◽  
Critical Determinant ◽  
Sh3 Domains ◽  
Lateral Membrane ◽  
Cell Height ◽  
Pi3k Activation ◽  
Phosphoinositide 3 Kinase

Maintaining the correct ratio of apical, basal, and lateral membrane domains is important for epithelial physiology. Here, we show that CD2AP is a critical determinant of epithelial membrane proportions. Depletion of CD2AP or phosphoinositide 3-kinase (PI3K) inhibition results in loss of F-actin and expansion of apical–basal domains, which comes at the expense of lateral membrane height in MDCK cells. We demonstrate that the SH3 domains of CD2AP bind to PI3K and are necessary for PI3K activity along lateral membranes and constraining cell area. Tethering the SH3 domains of CD2AP or p110γ to the membrane is sufficient to rescue CD2AP-knockdown phenotypes. CD2AP and PI3K are both upstream and downstream of actin polymerization. Since CD2AP binds to both actin filaments and PI3K, CD2AP might bridge actin assembly to PI3K activation to form a positive feedback loop to support lateral membrane extension. Our results provide insight into the squamous to cuboidal to columnar epithelial transitions seen in complex epithelial tissues in vivo.

A Novel Mechanism of Resistance to Epidermal Growth Factor Receptor Antagonism In vivo

2007 ◽  
Vol 67 (2) ◽  
pp. 665-673 ◽  
Author(s):  
Ashwani Rajput ◽  
Alan P. Koterba ◽  
Jeffrey I. Kreisberg ◽  
Jason M. Foster ◽  
James K.V. Willson ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Receptor Antagonism ◽  
Mechanism Of Resistance ◽  
Epidermal Growth

scholarly journals Antcin C fromAntrodia cinnamomeaProtects Liver Cells Against Free Radical-Induced Oxidative Stress and ApoptosisIn VitroandIn Vivothrough Nrf2-Dependent Mechanism

2013 ◽  
Vol 2013 ◽  
pp. 1-17 ◽  
Author(s):  
M. Gokila Vani ◽  
K. J. Senthil Kumar ◽  
Jiunn-Wang Liao ◽  
Shih-Chang Chien ◽  
Jeng-Leun Mau ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Transcriptional Activation ◽  
Liver Cells ◽  
Ros Generation ◽  
Antioxidant Genes ◽  
Pi3k Activation ◽  
Mice Liver ◽  
Induced Apoptosis

In this study, we investigated the cytoprotective effects of antcin C, a steroid-like compound isolated from Antrodia cinnamaomea against AAPH-induced oxidative stress and apoptosis in human hepatic HepG2 cells. Pretreatment with antcin C significantly protects hepatic cells from AAPH-induced cell death through the inhibition of ROS generation. Furthermore, AAPH-induced lipid peroxidation, ALT/AST secretion and GSH depletion was significantly inhibited by antcin C. The antioxidant potential of antcin C was correlated with induction of antioxidant genes including, HO-1, NQO-1,γ-GCLC, and SODviatranscriptional activation of Nrf2. The Nrf2 activation by antcin C is mediated by JNK1/2 and PI3K activation, whereas pharmacologic inhibition of JNK1/2 and PI3K abolished antcin C-induced Nrf2 activity. In addition, AAPH-induced apoptosis was significantly inhibited by antcin C through the down-regulation of pro-apoptotic factors including, Bax, cytochrome c, capase 9, -4, -12, -3, and PARP.In vivostudies also show that antcin C significantly protected mice liver from AAPH-induced hepatic injury as evidenced by reduction in hepatic enzymes in circulation. Further, immunocytochemistry analyses showed that antcin C significantly increased HO-1 and Nrf2 expression in mice liver tissues. These results strongly suggest that antcin C could protect liver cells from oxidative stress and cell deathviaNrf2/ARE activation.

scholarly journals The PI3K pathway drives the maturation of mast cells via microphthalmia transcription factor

Blood ◽  
2011 ◽  
Vol 118 (13) ◽  
pp. 3459-3469 ◽  
Author(s):  
Peilin Ma ◽  
Raghuveer Singh Mali ◽  
Veerendra Munugalavadla ◽  
Subha Krishnan ◽  
Baskar Ramdas ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Mast Cells ◽  
Pi3k Pathway ◽  
Regulatory Subunit ◽  
Growth And Survival ◽  
Src Homology 3 ◽  
Pi3k Activation ◽  
Src Homology ◽  
Microphthalmia Transcription Factor

Abstract Mast cell maturation is poorly understood. We show that enhanced PI3K activation results in accelerated maturation of mast cells by inducing the expression of microphthalmia transcription factor (Mitf). Conversely, loss of PI3K activation reduces the maturation of mast cells by inhibiting the activation of AKT, leading to reduced Mitf but enhanced Gata-2 expression and accumulation of Gr1+Mac1+ myeloid cells as opposed to mast cells. Consistently, overexpression of Mitf accelerates the maturation of mast cells, whereas Gata-2 overexpression mimics the loss of the PI3K phenotype. Expressing the full-length or the src homology 3– or BCR homology domain–deleted or shorter splice variant of the p85α regulatory subunit of PI3K or activated AKT or Mitf in p85α-deficient cells restores the maturation but not growth. Although deficiency of both SHIP and p85α rescues the maturation of SHIP−/− and p85α−/− mast cells and expression of Mitf; in vivo, mast cells are rescued in some, but not all tissues, due in part to defective KIT signaling, which is dependent on an intact src homology 3 and BCR homology domain of p85α. Thus, p85α-induced maturation, and growth and survival signals, in mast cells can be uncoupled.

BCR activation of PI3K is Vav-independent in murine B cells

2004 ◽  
Vol 32 (5) ◽  
pp. 781-784 ◽  
Author(s):  
E. Vigorito ◽  
E. Clayton ◽  
M. Turner
Keyword(s):  
B Cells ◽  
Tyrosine Kinases ◽  
Adaptor Proteins ◽  
Pleckstrin Homology Domain ◽  
Pi3k Activation ◽  
Lipid Product ◽  
Lipid Kinases ◽  
Phosphoinositide 3 Kinase

BCR (B-cell antigen receptor)-induced Ca2+ signalling is initiated by activation of tyrosine kinases, which in concert with adaptor proteins and lipid kinases regulate PLC (phospholipase C) γ2 activation. Vav and PI3K (phosphoinositide 3-kinase) are required for optimal Ca2+ responses, although it has not been established, in primary B-cells, if both proteins are components of the same pathway. In vitro evidence suggests that binding of the PI3K lipid product PIP3 to Vav pleckstrin homology domain contributes to Vav activation. However, pharmacological inhibition of PI3K by wortmannin or deletion of the p110δ catalytic subunit has no effect on Vav activation in response to BCR engagement, suggesting that this mechanism does not operate in vivo. We also show that PI3K recruitment to phosphorylated-tyrosine-containing complexes is Vav-independent. Taken together with our previous observation that protein kinase B phosphorylation is normal in Vav-deficient B-cells, we suggest that PI3K activation is Vav-independent in response to strong signals delivered by multivalent cross-linking.

scholarly journals Effects of Altering Aminoglycoside Structures on Bacterial Resistance Enzyme Activities

2011 ◽  
Vol 55 (7) ◽  
pp. 3207-3213 ◽  
Author(s):  
Keith D. Green ◽  
Wenjing Chen ◽  
Sylvie Garneau-Tsodikova
Keyword(s):  
Enzyme Activities ◽  
Bacterial Resistance ◽  
Bifunctional Enzyme ◽  
Mechanism Of Resistance

ABSTRACTAminoglycoside-modifying enzymes (AMEs) constitute the most prevalent mechanism of resistance to aminoglycosides by bacteria. We show that aminoglycosides can be doubly modified by the sequential actions of AMEs, with the activity of the second AME in most cases unaffected, decreased, or completely abolished. We demonstrate that the bifunctional enzyme AAC(3)-Ib/AAC(6′)-Ib′ can diacetylate gentamicin. Since single acetylation does not always inactivate the parent drugs completely, two modifications likely provide more-robust inactivationin vivo.

scholarly journals Resistance to platinum chemotherapy in lung adenocarcinoma is driven by a non-genetic, cell-cycle dependent mechanism

2020 ◽  
Author(s):  
Alvaro Gonzalez-Rajal ◽  
Rachael McCloy ◽  
Max Nobis ◽  
Kamila A Marzec ◽  
Venessa Chin ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Lung Adenocarcinoma ◽  
Parp Inhibitors ◽  
Genetic Mechanism ◽  
Cell Fates ◽  
Mechanism Of Resistance ◽  
Cycle Dependent ◽  
Platinum Chemotherapy

AbstractInnate resistance to platinum-based chemotherapies has significantly reduced their impact in lung adenocarcinoma. We previously used a pulse-based in vitro assay to unveil targetable signalling pathways associated with this resistant phenotype (Hastings et al., 2020). Here we advanced this model system and identify a non-genetic mechanism of resistance that drives recovery and regrowth in a subset of cells. Using RNAseq and a suite of biosensors to track single cell fates both in vitro and in vivo, we identified that early S phase cells have a greater capacity to repair damage over multiple generations. In contrast, cells in G1, late S or those treated with PARP inhibitors, were unable to sufficiently repair the damage and underwent prolonged S/G2 phase arrest and senescence. These data indicate that there is a fundamental non-genetic mechanism of resistance in lung adenocarcinoma that is dependent on the cell cycle stage at the time of cisplatin exposure.

CD38 as a novel immune checkpoint and a mechanism of resistance to the blockade of the PD-1/PD-L1 axis.

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 79-79 ◽  
Author(s):  
Limo Chen ◽  
Lauren Averett Byers ◽  
Stephen Ullrich ◽  
Ignacio Ivan Wistuba ◽  
Xiao-Feng Qin ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Tumor Cells ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
High Rate ◽  
Positive Staining ◽  
Antibody Treatment ◽  
Mechanism Of Resistance

79 Background: Although immune checkpoint inhibitors including PD-L1 blockade provide significant clinical benefit for patients with lung cancer, barriers to immunotherapy clinical successes have been due to a high rate of resistance. The therapeutic improvement requires a thorough understanding of the biological process of resistance. Until recently, there have been only a few studies reporting the mechanisms of resistance to PD-L1 blockade. The mechanistic basis remains poorly defined. Methods: In multiple immunocompetent syngeneic and K-rasLA1/+p53R172H?g/+ spontaneous animal models of lung cancer, we have explored the resistance mechanisms using pharmacological and genetic approaches (monoclonal antibody treatment and CRISPR/Cas9-mediated editing). The molecular and immune profiles of the tumor microenvironment were evaluated. More importantly, to determine the applicability to patients with lung cancer, we analyzed 259 patients’ specimens with IHC staining and mined many immune markers in TCGA adeno and squamous datasets. Results: We identified the up-regulation of CD38 on tumor cells as well as enrichment of CD38highTregs and CD38highMDSCs in tumor as the markers of treatment resistance. We observed the same resistance mechanism caused by CD38 in PD-L1 KO mice bearing PD-L1 KO Lewis lung tumors edited with the CRISPR/Cas9 system. Furthermore, by manipulating CD38 on a panel of lung cancer cell lines, in vitro and in vivo data demonstrates that CD38 inhibits CD8+ T cell proliferation, antitumor cytokine secretion, and tumor cell killing capability. To test whether CD38 blockade might be therapeutically efficacious to anti-PD-L1 resistance, we applied the combination therapy of anti-CD38 and anti-PD-L1 and demonstrated dramatic therapeutic benefit on primary tumor growth and metastasis. Additionally, in 259 lung patients, 18.5% of cases exhibited positive staining for CD38 on tumor cells, showing a great potential benefit for treating lung patients. Conclusions: CD38 is defined as a novel immune checkpoint and acts as a mechanism of resistance in the context of PD-L1 therapy. Targeting this novel immune checkpoint may broaden the benefit of PD-L1/PD-1 axis blockade for lung cancer treatment.

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