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SHP2 cancer

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
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 )...
August 13, 2018: Nature Cell Biology
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
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 (MEK-Is) typically occurs via induction of genes for different receptor tyrosine kinases (RTKs) 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 MEK-I inhibited the proliferation of multiple cancer cell lines in vitro. PTPN11 knockdown/MEK-I treatment had similar effects, while expressing SHP099 binding-defective PTPN11 mutants conferred resistance, demonstrating that SHP099 is on-target...
July 25, 2018: Cancer Discovery
Yuncang Yuan, Guoxiang Qi, Hao Shen, Aizhen Guo, Fuao Cao, Yan Zhu, Chunjie Xiao, Wenjun Chang, Shangyong Zheng
In recent years, protein-protein interactions have become an attractive candidate for identifying biomarkers and drug targets for various diseases. However, WD40 repeat (WDR) domain proteins, some of the most abundant mediators of protein interactions, are largely unexplored. In this study, 57 of 361 known WDR proteins were identified as hub nodes, and a hub (WDR54) with elevated mRNA in colorectal cancer (CRC) was selected for further study. Immunohistochemistry of specimens from 945 patients confirmed the elevated expression of WDR54 in CRC, and we found that patients with WDR54-high tumors typically had a shorter disease-specific survival (DSS) than those with WDR54-low tumors, especially for the subgroup without well-differentiated tumors...
July 10, 2018: International Journal of Cancer. Journal International du Cancer
Chen Kan, Fan Yang, Siying Wang
Stem cells, including embryonic stem cells (ESCs) and adult stem cells, play a central role in mammal organism development and homeostasis. They have two unique properties: the capacity for self-renewal and the ability to differentiate into many specialized cell types. Src homology region 2- (SH2-) containing protein tyrosine phosphatase 2 (SHP-2), a nonreceptor protein tyrosine phosphatase encoded by protein tyrosine phosphatase nonreceptor type 11 gene (PTPN11), regulates multicellular differentiation, proliferation, and survival through numerous conserved signal pathways...
2018: Stem Cells International
Jun Cao, Yu-Qing Huang, Jiao-Sun, Xia-Bin Lan, Ming-Hua Ge
Some thyroid carcinomas (TCs) have a violent biological behavior and poor prognosis, and lacking of effective molecular markers is still the main obstacle for clinical stratified diagnosis and treatment of TC. The aim of the study was to discover the clinicopathological and prognostic implications of Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2) and Hook microtubule tethering protein 1(Hook1) expression in TC. The expression of SHP2 and Hook1was detected by immunohistochemistry on tissue microarrays from 313 primary TC who underwent surgery during January 2006 and January 2010 in Zhejiang Cancer Hospital...
June 25, 2018: Human Pathology
Cijo George Vazhappilly, Ekram Saleh, Wafaa Ramadan, Varsha Menon, Aya Mudhafar Al-Azawi, Hamadeh Tarazi, Hajjaj Abdu-Allah, Abdel-Nasser El-Shorbagi, Raafat El-Awady
Kinases and phosphatases are important players in growth signaling and are involved in cancer development. For development of targeted cancer therapy, attention is given to kinases rather than phosphatases inhibitors. Src homology region 2 domain-containing protein tyrosine phosphatase2 (SHP2) is overexpressed in different types of cancers. We investigated the SHP2-inhibitory effects of two new 5-aminosalicylate-4-thiazolinones in human cervical (HeLa) and breast (MCF-7 & MDA-MB-231) cancer cells. In-silico molecular docking showed preferential affinity of the two compounds towards the catalytic over the allosteric site of SHP2...
June 27, 2018: Investigational New Drugs
Mathurin Dorel, Bertram Klinger, Torsten Gross, Anja Sieber, Anirudh Prahallad, Evert Bosdriesz, Lodewyk Wessels, Nils Blüthgen
Motivation: Intracellular signalling is realised by complex signalling networks which are almost impossible to understand without network models, especially if feedbacks are involved. Modular Response Analysis (MRA) is a convenient modelling method to study signalling networks in various contexts. Results: We developed the software package STASNet that provides an augmented and extended version of MRA suited to model signalling networks from incomplete perturbation schemes and multi-perturbation data...
June 19, 2018: Bioinformatics
Chuan Chen, Tongdan Xue, Peng Fan, Linlin Meng, Jingjing Wei, Duqiang Luo
Fumosorinone (Fumos) isolated from entomogenous fungi Isaria fumosorosea exhibited selective inhibition of Src homology phosphotyrosine phosphatase 2 inhibitor (Shp2) in our previous study. The purpose of the present study was to investigate the effects of Fumos on cell cycle arrest, tumor cell migration and the in vitro antiproliferative activity of Fumos alone or in combination with the commonly used cytotoxic drugs 5-fluoracil (5-FU) and p38 inhibitor SB203580. Fumos exhibited cytotoxicity against selected human cancel lines, including HeLa, MDA-MB-231 and MDA-MB-453 cell lines...
June 2018: Oncology Letters
Diana F Rojas-Rengifo, Maria Camila Alvarez-Silva, Cindy P Ulloa-Guerrero, Vanessa Lucía Nuñez-Velez, Maria Del Pilar Delgado, Sonia Milena Aguilera, Harold Castro, Carlos Alberto Jaramillo, Andrés Fernando González Barrios
The Helicobacter pylori cytotoxin-associated gene A (CagA) is known for causing gastroduodenal diseases, such as atrophic gastritis and peptic ulcerations. Furthermore Helicobacter pylori CagA positive strains has been reported as one of the main risk factors for gastric cancer (Parsonnet et al., 1997). Structural variations in the CagA structure can alter its affinity with the host proteins, inducing differences in the pathogenicity of H. pylori. CagA N-terminal region is characterized for be conserved among all H...
May 25, 2018: Computational Biology and Chemistry
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
The role of KRAS, when activated through canonical mutations, has been well established in cancer1 . Here we explore a secondary means of KRAS activation in cancer: focal high-level amplification of the KRAS gene in the absence of coding mutations. These amplifications occur most commonly in esophageal, gastric and ovarian adenocarcinomas2-4 . KRAS-amplified gastric cancer models show marked overexpression of the KRAS protein and are insensitive to MAPK blockade owing to their capacity to adaptively respond by rapidly increasing KRAS-GTP levels...
July 2018: Nature Medicine
Dietrich A Ruess, Guus J Heynen, Katrin J Ciecielski, Jiaoyu Ai, Alexandra Berninger, Derya Kabacaoglu, Kivanc Görgülü, Zahra Dantes, Sonja M Wörmann, Kalliope N Diakopoulos, Angeliki F Karpathaki, Marlena Kowalska, Ezgi Kaya-Aksoy, Liang Song, Eveline A Zeeuw van der Laan, María P López-Alberca, Marc Nazaré, Maximilian Reichert, Dieter Saur, Mert M Erkan, Ulrich T Hopt, Bruno Sainz, Walter Birchmeier, Roland M Schmid, Marina Lesina, Hana Algül
The ubiquitously expressed non-receptor protein tyrosine phosphatase SHP2, encoded by PTPN11, is involved in signal transduction downstream of multiple growth factor, cytokine and integrin receptors1 . Its requirement for complete RAS-MAPK activation and its role as a negative regulator of JAK-STAT signaling have established SHP2 as an essential player in oncogenic signaling pathways1-7 . Recently, a novel potent allosteric SHP2 inhibitor was presented as a viable therapeutic option for receptor tyrosine kinase-driven cancers, but was shown to be ineffective in KRAS-mutant tumor cell lines in vitro8 ...
July 2018: Nature Medicine
Sara Mainardi, Antonio Mulero-Sánchez, Anirudh Prahallad, Giovanni Germano, Astrid Bosma, Paul Krimpenfort, Cor Lieftink, Jeffrey D Steinberg, Niels de Wit, Samuel Gonçalves-Ribeiro, Ernest Nadal, Alberto Bardelli, Alberto Villanueva, Rene Bernards
RAS mutations are frequent in human cancer, especially in pancreatic, colorectal and non-small-cell lung cancers (NSCLCs)1-3 . Inhibition of the RAS oncoproteins has proven difficult4 , and attempts to target downstream effectors5-7 have been hampered by the activation of compensatory resistance mechanisms8 . It is also well established that KRAS-mutant tumors are insensitive to inhibition of upstream growth factor receptor signaling. Thus, epidermal growth factor receptor antibody therapy is only effective in KRAS wild-type colon cancers9,10 ...
July 2018: Nature Medicine
Sumit Bhattacharyya, Leo Feferman, Xiaorui Han, Yilan Ouyang, Fuming Zhang, Robert J Linhardt, Joanne K Tobacman
Epidermal growth factor receptor (EGFR) has a crucial role in cell differentiation and proliferation and cancer, and its expression appears to be up-regulated when arylsulfatase B (ARSB or GalNAc-4-sulfatase) is reduced. ARSB removes 4-sulfate groups from the nonreducing end of dermatan sulfate and chondroitin 4-sulfate (C4S), and its decreased expression has previously been reported to inhibit the activity of the ubiquitous protein-tyrosine phosphatase, nonreceptor type 11 (SHP2 or PTPN11). However, the mechanism by which decline in ARSB leads to decline in SHP2 activity is unclear...
July 13, 2018: Journal of Biological Chemistry
ZhongQian Hu, Bin Yang, Tiankuan Li, Jia Li
Background: Contrast-enhanced ultrasound imaging has been widely used in the ultrasound diagnosis of a variety of tumours with high diagnostic accuracy, especially in patients with hepatic carcinoma, while its application is rarely reported in thyroid cancer. The currently used ultrasound contrast agents, microbubbles, cannot be targeted to molecular markers expressed in tumour cells due to their big size, leading to a big challenge for ultrasound molecular imaging. Phase-changeable perfluorocarbon nanoparticles may resolve the penetrability limitation of microbubbles and serve as a promising probe for ultrasound molecular imaging...
2018: Contrast Media & Molecular Imaging
Jacey J Liu, Yanjie Li, Wendy S Chen, Yan Liang, Gaowei Wang, Min Zong, Kota Kaneko, Ruiyun Xu, Michael Karin, Gen-Sheng Feng
BACKGROUND & AIMS: Shp2 is an SH2-tyrosine phosphatase acting downstream of receptor tyrosine kinases (RTKs). Most recent data demonstrated a liver tumor-suppressing role for Shp2, as ablating Shp2 in hepatocytes aggravated hepatocellular carcinoma (HCC) induced by chemical carcinogens or Pten loss. We further investigated the effect of Shp2 deficiency on liver tumorigenesis driven by classical oncoproteins c-Met (receptor for HGF), β-catenin and PIK3CA. METHODS: We performed hydrodynamic tail vein injection of two pairs of plasmids expressing c-Met and ΔN90-β-catenin (MET/CAT), or c-Met and PIK3CAH1047R (MET/PIK), into WT and Shp2hep-/- mice...
July 2018: Journal of Hepatology
Leila Dardaei, Hui Qin Wang, Manrose Singh, Paul Fordjour, Katherine X Shaw, Satoshi Yoda, Grainne Kerr, Kristine Yu, Jinsheng Liang, Yichen Cao, Yan Chen, Michael S Lawrence, Adam Langenbucher, Justin F Gainor, Luc Friboulet, Ibiayi Dagogo-Jack, David T Myers, Emma Labrot, David Ruddy, Melissa Parks, Dana Lee, Richard H DiCecca, Susan Moody, Huaixiang Hao, Morvarid Mohseni, Matthew LaMarche, Juliet Williams, Keith Hoffmaster, Giordano Caponigro, Alice T Shaw, Aaron N Hata, Cyril H Benes, Fang Li, Jeffrey A Engelman
Most anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung tumors initially respond to small-molecule ALK inhibitors, but drug resistance often develops. Of tumors that develop resistance to highly potent second-generation ALK inhibitors, approximately half harbor resistance mutations in ALK, while the other half have other mechanisms underlying resistance. Members of the latter group often have activation of at least one of several different tyrosine kinases driving resistance. Such tumors are not expected to respond to lorlatinib-a third-generation inhibitor targeting ALK that is able to overcome all clinically identified resistant mutations in ALK-and further therapeutic options are limited...
May 2018: Nature Medicine
Wen-Yan Jin, Ying Ma, Wei-Ya Li, Hong-Lian Li, Run-Ling Wang
SHP2 is a potential target for the development of novel therapies for SHP2-dependent cancers. In our research, with the aid of the 'Receptor-Ligand Pharmacophore' technique, a 3D-QSAR method was carried out to explore structure activity relationship of SHP2 allosteric inhibitors. Structure-based drug design was employed to optimize SHP099, an efficacious, potent, and selective SHP2 allosteric inhibitor. A novel class of selective SHP2 allosteric inhibitors was discovered by using the powerful 'SBP', 'ADMET' and 'CDOCKER' techniques...
April 2018: Computational Biology and Chemistry
Yao Liu, Huan Jing, Xiaoxing Kou, Chider Chen, Dawei Liu, Yan Jin, Li Lu, Songtao Shi
Programmed cell death-1 (PD-1) belongs to an inhibitory signaling pathway capable of maintaining central and peripheral immune tolerance. Blockage of PD-1 has been identified as a promising immunotherapeutic approach for cancer and chronic infectious diseases. However, it is unknown whether PD-1 pathway regulates stem cell function. It is generally believed that mesenchymal stem cells (MSCs) produce PD-1 ligand, but fail to express PD-1. In this study, we show that neural crest-derived MSCs from dental pulp (MSC-DP), but not MSCs from bone marrow, expressed PD-1...
July 2018: Cell Death and Differentiation
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