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SHP2 cancer

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https://www.readbyqxmd.com/read/30473379/integrin-linked-kinase-ilk-and-src-homology-2-domain-containing-phosphatase-2-shp2-novel-targets-in-egfr-mutation-positive-non-small-cell-lung-cancer-nsclc
#1
Niki Karachaliou, Andres Felipe Cardona, Jillian Wilhelmina Paulina Bracht, Erika Aldeguer, Ana Drozdowskyj, Manuel Fernandez-Bruno, Imane Chaib, Jordi Berenguer, Mariacarmela Santarpia, Masaoki Ito, Jordi Codony-Servat, Rafael Rosell
BACKGROUND: The activation of multiple signaling pathways jeopardizes the clinical efficacy of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutation positive non-small cell lung cancer (NSCLC). Integrin-linked kinase (ILK) regulates the interactions between tumor cells and extracellular environment to activate signaling pathways and promote cell proliferation, migration, and epithelial-mesenchymal transition. Src homology 2 domain-containing phosphatase 2 (SHP2) is essential for receptor tyrosine kinase signaling and mitogen-activated protein kinase (MAPK) pathway activation...
November 22, 2018: EBioMedicine
https://www.readbyqxmd.com/read/30467378/conditional-knockout-of-shp2-in-erbb2-transgenic-mice-or-inhibition-in-her2-amplified-breast-cancer-cell-lines-blocks-oncogene-expression-and-tumorigenesis
#2
Hua Zhao, Elisha Martin, Fatimah Matalkah, Neal Shah, Alexey Ivanov, J Michael Ruppert, Paul R Lockman, Yehenew M Agazie
Overexpression of the human epidermal growth factor receptor 2 (HER2) is the cause of HER2-positive breast cancer (BC). Although HER2-inactivating therapies have benefited BC patients, development of resistance and disease recurrence have been the major clinical problems, pointing to a need for alternative therapeutic strategies. For that to happen, proteins that play critical roles in the biology of HER2-induced tumorigenesis have to be identified and characterized. Here, we show that the Src homology phosphotyrosyl phosphatase 2 (Shp2) encoded by the Ptpn11 gene is a requisite for ErbB2-induced tumorigenesis...
November 22, 2018: Oncogene
https://www.readbyqxmd.com/read/30461272/total-synthesis-biological-evaluation-and-target-identification-of-rare-abies-sesquiterpenoids
#3
Dexter C Davis, Dominic G Hoch, Li Wu, Daniel Abegg, Brandon S Martin, Zhong-Yin Zhang, Alexander Adibekian, Mingji Dai
Abiespiroside A (1), beshanzuenone C (2), and beshanzuenone D (3) belong to the Abies sesquiterpenoid family. Beshanzue-nones C (2) and D (3) are isolated from the critically endangered Chinese fir tree species Abies beshanzuensis and demon-strated weak inhibiting activity against protein tyrosine phosphatase 1B (PTP1B). We describe herein the first total synthe-ses of these Abies sesquiterpenoids relying on the sustainable and inexpensive chiral pool molecule (+)-carvone. The synthe-ses feature a palladium-catalyzed hydrocarbonylative lactonization to install the 6,6-fused bicyclic ring system and a Dreiding-Schmidt reaction to build the oxaspirolactone moiety of these target molecules...
November 21, 2018: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/30430347/probing-the-dynamic-mechanism-of-uncommon-allosteric-inhibitors-optimized-to-enhance-drug-selectivity-of-shp2-with-therapeutic-potential-for-cancer-treatment
#4
Abdolkarim Farrokhzadeh, Farideh Badichi Akher, Mahmoud E S Soliman
There is currently considerable interest in SHP2 as a potential target for treatment of cancer. Mutation in SHP2, particularly the E76A mutation, has been found to seriously confer the phosphatase high activity. Recently, two compounds, 1 and 23, have been reported as potent allosteric inhibitors of both SHP2 wild type (SHP2WT ) and the E76A mutant (SHP2E76A ), with higher activity than other inhibitors. However, the structural and dynamic implications of their inhibitory mechanisms are yet unexplored which deserve further attention...
November 15, 2018: Applied Biochemistry and Biotechnology
https://www.readbyqxmd.com/read/30398108/the-landscape-of-protein-tyrosine-phosphatase-shp2-and-cancer
#5
Ashfaq Ur Rehman, Mueed Ur Rehman, K M Tahir, Shah Saud, Hao Liu, Dong Song, Pinky Sultana, Abdul Wadood, Hai-Feng Chen
Role of Shp2: The dysregulation of cell signaling cascades associated with the cell differentiation and growth, due to the deletion, insertion or point mutation in specific amino acids which alters the intrinsic conformation of the protein, can ultimately lead to a fatal cancer disease. The protein tyrosine phosphatase has been recognized as a key regulator of extracellular stimuli such as cytokine receptor and receptor tyrosine kinase signaling. In the last era, the PTPN11 gene (encode a Shp2 protein) and its association with acute myeloid, juvenile myelomonocytic, and B-cell acute lymphoblastic leukemia, Noonan syndrome, and myelodysplastic has been recognized, the cause of such deadly disease due to the occurrence of germline mutations in the interface of PTP and SH2 domain...
November 5, 2018: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/30389797/-combination-cancer-immunotherapy-targeting-pd-1-and-gitr-can-rescue-cd8-t-cell-dysfunction-and-maintain-memory-phenotype
#6
Bei Wang, Wen Zhang, Vladimir Jankovic, Jacquelynn Golubov, Patrick Poon, Erin M Oswald, Cagan Gurer, Joyce Wei, Ilyssa Ramos, Qi Wu, Janelle Waite, Min Ni, Christina Adler, Yi Wei, Lynn Macdonald, Tracey Rowlands, Susannah Brydges, Jean Siao, William Poueymirou, Douglas MacDonald, George D Yancopoulos, Matthew A Sleeman, Andrew J Murphy, Dimitris Skokos
Most patients with cancer do not develop durable antitumor responses after programmed cell death protein 1 (PD-1) or programmed cell death ligand 1(PD-L1) checkpoint inhibition monotherapy because of an ephemeral reversal of T cell dysfunction and failure to promote long-lasting immunological T cell memory. Activating costimulatory pathways to induce stronger T cell activation may improve the efficacy of checkpoint inhibition and lead to durable antitumor responses. We performed single-cell RNA sequencing of more than 2000 tumor-infiltrating CD8+ T cells in mice receiving both PD-1 and GITR (glucocorticoid-induced tumor necrosis factor receptor-related protein) antibodies and found that this combination synergistically enhanced the effector function of expanded CD8+ T cells by restoring the balance of key homeostatic regulators CD226 and T cell immunoreceptor with Ig and ITIM domains (TIGIT), leading to a robust survival benefit...
November 2, 2018: Science Immunology
https://www.readbyqxmd.com/read/30375388/structural-reorganization-of-shp2-by-oncogenic-mutations-and-implications-for-oncoprotein-resistance-to-allosteric-inhibition
#7
Jonathan R LaRochelle, Michelle Fodor, Vidyasiri Vemulapalli, Morvarid Mohseni, Ping Wang, Travis Stams, Matthew J LaMarche, Rajiv Chopra, Michael G Acker, Stephen C Blacklow
Activating mutations in PTPN11, encoding the cytosolic protein tyrosine phosphatase SHP2, result in developmental disorders and act as oncogenic drivers in patients with hematologic cancers. The allosteric inhibitor SHP099 stabilizes the wild-type SHP2 enzyme in an autoinhibited conformation that is itself destabilized by oncogenic mutations. Here, we report the impact of the highly activated and most frequently observed mutation, E76K, on the structure of SHP2, and investigate the effect of E76K and other oncogenic mutations on allosteric inhibition by SHP099...
October 30, 2018: Nature Communications
https://www.readbyqxmd.com/read/30375376/mechanism-of-activating-mutations-and-allosteric-drug-inhibition-of-the-phosphatase-shp2
#8
Ricardo A P Pádua, Yizhi Sun, Ingrid Marko, Warintra Pitsawong, John B Stiller, Renee Otten, Dorothee Kern
Protein tyrosine phosphatase SHP2 functions as a key regulator of cell cycle control, and activating mutations cause several cancers. Here, we dissect the energy landscape of wild-type SHP2 and the oncogenic mutation E76K. NMR spectroscopy and X-ray crystallography reveal that wild-type SHP2 exchanges between closed, inactive and open, active conformations. E76K mutation shifts this equilibrium toward the open state. The previously unknown open conformation is characterized, including the active-site WPD loop in the inward and outward conformations...
October 30, 2018: Nature Communications
https://www.readbyqxmd.com/read/30374120/evaluating-the-origin-and-virulence-of-a-helicobacter-pylori-caga-positive-strain-isolated-from-a-non-human-primate
#9
Kana Hashi, Chihiro Imai, Koji Yahara, Kamrunnesa Tahmina, Takeru Hayashi, Takeshi Azuma, Takako Miyabe-Nishiwaki, Hideyuki Sato, Masao Matsuoka, Sachi Niimi, Munehiro Okamoto, Masanori Hatakeyama
Helicobacter pylori cagA-positive strains are critically involved in the development of gastric cancer. Upon delivery into gastric epithelial cells via type IV secretion, the cagA-encoded CagA interacts with and thereby perturbs the pro-oncogenic phosphatase SHP2 and the polarity-regulating kinase PAR1b via the tyrosine-phosphorylated EPIYA-C/D segment and the CM sequence, respectively. Importantly, sequences spanning these binding regions exhibit variations among CagA proteins, which influence the pathobiological/oncogenic potential of individual CagA...
October 29, 2018: Scientific Reports
https://www.readbyqxmd.com/read/30355677/ptpn11-plays-oncogenic-roles-and-is-a-therapeutic-target-for-braf-wild-type-melanomas
#10
Kristen S Hill, Evan R Roberts, Xue Wang, Ellen Marin, Taeeun D Park, Sorany Son, Yuan Ren, Bin Fang, Sean Yoder, Sungjune Kim, Lixin Wan, Amod A Sarnaik, John M Koomen, Jane L Messina, Jamie K Teer, Youngchul Kim, Jie Wu, Charles E Chalfant, Minjung Kim
Melanoma is one of the most highly mutated cancer types. To identify functional drivers of melanoma, we searched for cross-species conserved mutations utilizing a mouse melanoma model driven by loss of PTEN and CDKN2A, and identified mutations in Kras, Erbb3, and Ptpn11. PTPN11 encodes the SHP2 protein tyrosine phosphatase (PTP) that activates the RAS/RAF/MAPK pathway. Although PTPN11 is an oncogene in leukemia, lung, and breast cancers, its roles in melanoma are not clear. In this study, we found that PTPN11 is frequently activated in human melanoma specimens and cell lines and is required for full RAS/RAF/MAPK signaling activation in BRAF wild-type (either NRAS mutant or wild-type) melanoma cells...
October 24, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/30343889/immune-inhibitory-receptor-lilrb2-is-critical-for-the-endometrial-cancer-progression
#11
Hongfang Shao, Li Ma, Feng Jin, Yang Zhou, Minfang Tao, Yincheng Teng
Although leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2) is known as an immune inhibitory receptor to suppress the immune system, its function in cancer development remains largely unknown. Herein, we provide the first body of information showing that LILRB2 is highly expressed in the endometrial cancer. More importantly, the expression levels of LILRB2 are inversely correlated with the overall patients' survival. Knockdown of LILRB2 results in a dramatic decrease in the proliferation, colony formation and migration in several endometrial cancer cell lines in vitro...
October 18, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/30319552/the-anti-tumoral-properties-of-orexin-hypocretin-hypothalamic-neuropeptides-an-unexpected-therapeutic-role
#12
REVIEW
Alain Couvineau, Stéphanie Dayot, Pascal Nicole, Valérie Gratio, Vinciane Rebours, Anne Couvelard, Thierry Voisin
Orexins (OxA and OxB) also termed hypocretins are hypothalamic neuropeptides involved in central nervous system (CNS) to control the sleep/wake process which is mediated by two G protein-coupled receptor subtypes, OX1R, and OX2R. Beside these central effects, orexins also play a role in various peripheral organs such as the intestine, pancreas, adrenal glands, kidney, adipose tissue and reproductive tract.In the past few years, an unexpected anti-tumoral role of orexins mediated by a new signaling pathway involving the presence of two immunoreceptor tyrosine-based inhibitory motifs (ITIM) in both orexin receptors subtypes, the recruitment of the phosphotyrosine phosphatase SHP2 and the induction of mitochondrial apoptosis has been elucidated...
2018: Frontiers in Endocrinology
https://www.readbyqxmd.com/read/30279193/shipping-out-mek-inhibitor-resistance-with-shp2-inhibitors
#13
Pedro Torres-Ayuso, John Brognard
<b/> RAS is one of the most frequently altered oncogenes, yet RAS-driven tumors are largely refractory to anticancer therapies. Fedele and colleagues demonstrate that SHP2 inhibitors prevent adaptive MEK inhibitor resistance; therefore, combining MEK and SHP2 inhibitors represents an exciting new therapeutic approach for the treatment of RAS-driven cancers. Cancer Discov; 8(10); 1210-2. ©2018 AACR. See related article by Fedele et al., p. 1237 .
October 2018: Cancer Discovery
https://www.readbyqxmd.com/read/30247891/proteomic-identification-of-protein-tyrosine-phosphatase-and-substrate-interactions-in-living-mammalian-cells-by-genetic-encoding-of-irreversible-enzyme-inhibitors
#14
Hongting Tang, Zhen Dai, Xuewen Qin, Wenkang Cai, Liming Hu, Yujia Huang, Wenbing Cao, Fan Yang, Chu Wang, Tao Liu
Protein tyrosine phosphatases (PTPs) play critical roles in cell signaling pathways, but identification of unknown PTPs for a given substrate in live cells remain technically challenging. Here, we synthesized a series of tyrosine-based irreversible PTP inhibitors and characterized by site-specific encoding on substrate proteins in cells with an expanded genetic code. By fine-tuning the chemical reactivity, we identified optimal active amino acid probes to covalently cross-link a PTP and its substrate both in vitro and in mammalian cells...
October 17, 2018: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/30208623/protein-tyrosine-phosphatases-as-potential-regulators-of-stat3-signaling
#15
REVIEW
Mihwa Kim, Liza D Morales, Ik-Soon Jang, Yong-Yeon Cho, Dae Joon Kim
The signal transducer and activator of transcription 3 (STAT3) protein is a major transcription factor involved in many cellular processes, such as cell growth and proliferation, differentiation, migration, and cell death or cell apoptosis. It is activated in response to a variety of extracellular stimuli including cytokines and growth factors. The aberrant activation of STAT3 contributes to several human diseases, particularly cancer. Consequently, STAT3-mediated signaling continues to be extensively studied in order to identify potential targets for the development of new and more effective clinical therapeutics...
September 11, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/30186742/off-target-inhibition-by-active-site-targeting-shp2-inhibitors
#16
Ryouhei Tsutsumi, Hao Ran, Benjamin G Neel
Due to the involvement of SHP2 (SH2 domain-containing protein-tyrosine phosphatase) in human disease, including Noonan syndrome and cancer, several inhibitors targeting SHP2 have been developed. Here, we report that the commonly used SHP2 inhibitor NSC-87877 does not exhibit robust inhibitory effects on growth factor-dependent MAPK (mitogen-activated protein kinase) pathway activation and that the recently developed active site-targeting SHP2 inhibitors IIB-08, 11a-1, and GS-493 show off-target effects on ligand-evoked activation/trans-phosphorylation of the PDGFRβ (platelet-derived growth factor receptor β)...
September 2018: FEBS Open Bio
https://www.readbyqxmd.com/read/30107178/therapeutic-ablation-of-gain-of-function-mutant-p53-in-colorectal-cancer-inhibits-stat3-mediated-tumor-growth-and-invasion
#17
Ramona Schulz-Heddergott, Nadine Stark, Shelley J Edmunds, Jinyu Li, Lena-Christin Conradi, Hanibal Bohnenberger, Fatih Ceteci, Florian R Greten, Matthias Dobbelstein, Ute M Moll
Over half of colorectal cancers (CRCs) harbor TP53 missense mutations (mutp53). We show that the most common mutp53 allele R248Q (p53Q ) exerts gain of function (GOF) and creates tumor dependence in mouse CRC models. mutp53 protein binds Stat3 and enhances activating Stat3 phosphorylation by displacing the phosphatase SHP2. Ablation of the p53Q allele suppressed Jak2/Stat3 signaling, growth, and invasiveness of established, mutp53-driven tumors. Treating tumor-bearing mice with an HSP90 inhibitor suppressed mutp53 levels and tumor growth...
August 13, 2018: Cancer Cell
https://www.readbyqxmd.com/read/30104724/ras-nucleotide-cycling-underlies-the-shp2-phosphatase-dependence-of-mutant-braf-nf1-and-ras-driven-cancers
#18
Robert J Nichols, Franziska Haderk, Carlos Stahlhut, Christopher J Schulze, Golzar Hemmati, David Wildes, Christos Tzitzilonis, Kasia Mordec, Abby Marquez, Jason Romero, Tientien Hsieh, Aubhishek Zaman, Victor Olivas, Caroline McCoach, Collin M Blakely, Zhengping Wang, Gert Kiss, Elena S Koltun, Adrian L Gill, Mallika Singh, Mark A Goldsmith, Jacqueline A M Smith, Trever G Bivona
Oncogenic alterations in the RAS/RAF/MEK/ERK pathway drive the growth of a wide spectrum of cancers. While BRAF and MEK inhibitors are efficacious against BRAFV600E -driven cancers, effective targeted therapies are lacking for most cancers driven by other pathway alterations, including non-V600E oncogenic BRAF, RAS GTPase-activating protein (GAP) NF1 (neurofibromin 1) loss and oncogenic KRAS. Here, we show that targeting the SHP2 phosphatase (encoded by PTPN11) with RMC-4550, a small-molecule allosteric inhibitor, is effective in human cancer models bearing RAS-GTP-dependent oncogenic BRAF (for example, class 3 BRAF mutants), NF1 loss or nucleotide-cycling oncogenic RAS (for example, KRASG12C )...
September 2018: Nature Cell Biology
https://www.readbyqxmd.com/read/30093730/author-correction-targeting-wild-type-kras-amplified-gastroesophageal-cancer-through-combined-mek-and-shp2-inhibition
#19
Gabrielle S Wong, Jin Zhou, Jie Bin Liu, Zhong Wu, Xinsen Xu, Tianxia Li, David Xu, Steven E Schumacher, Jens Puschhof, James McFarland, Charles Zou, Austin Dulak, Les Henderson, Peng Xu, Emily O'Day, Rachel Rendak, Wei-Li Liao, Fabiola Cecchi, Todd Hembrough, Sarit Schwartz, Christopher Szeto, Anil K Rustgi, Kwok-Kin Wong, J Alan Diehl, Karin Jensen, Francesco Graziano, Annamaria Ruzzo, Shaunt Fereshetian, Philipp Mertins, Steven A Carr, Rameen Beroukhim, Kenichi Nakamura, Eiji Oki, Masayuki Watanabe, Hideo Baba, Yu Imamura, Daniel Catenacci, Adam J Bass
In the Supplementary Information originally published with this article, a lane was missing in the β-actin blot in Supplementary Fig. 2. The lane has been added. The error has been corrected in the Supplementary Information associated with this article.
August 9, 2018: Nature Medicine
https://www.readbyqxmd.com/read/30045908/shp2-inhibition-prevents-adaptive-resistance-to-mek-inhibitors-in-multiple-cancer-models
#20
Carmine Fedele, Hao Ran, Brian Diskin, Wei Wei, Jayu Jen, Mitchell J Geer, Kiyomi Araki, Ugur Ozerdem, Diane M Simeone, George Miller, Benjamin G Neel, Kwan Ho Tang
Adaptive resistance to MEK inhibitors (MEKi) typically occurs via induction of genes for different receptor tyrosine kinases (RTK) and/or their ligands, even in tumors of the same histotype, making combination strategies challenging. SHP2 ( PTPN11 ) is required for RAS/ERK pathway activation by most RTKs and might provide a common resistance node. We found that combining the SHP2 inhibitor SHP099 with a MEKi inhibited the proliferation of multiple cancer cell lines in vitro PTPN11 knockdown/MEKi treatment had similar effects, whereas expressing SHP099 binding-defective PTPN11 mutants conferred resistance, demonstrating that SHP099 is on-target...
October 2018: Cancer Discovery
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