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Tyrosine kinases

Michael Bartoschek, Kristian Pietras
The development and progression of a tumor depends on the close interaction of malignant cells and the supportive and suppressive tumor microenvironment. Paracrine signaling enables tumor cells to shape the surrounding tissue in order to decrease recognition by the immune system, attract blood vessels to fuel growth, change metabolic programs and induce wound healing programs. In this study, we investigate the role of the platelet-derived growth factor (PDGF) family members PDGFA, PDGFB, PDGFC and PDGFD and their cognate tyrosine kinase receptors PDGFRA and PDGFRB, using publicly available data from The Cancer Genome Atlas and the Human Protein Atlas...
June 19, 2018: Biochemical and Biophysical Research Communications
Rahul Ladwa, Victoria Atkinson
AIM: Improved systemic treatment has improved the prognosis of metastatic melanoma (MM). However, brain metastases (BMs) are a frequent complication. We aimed to explore the outcome of these patients with modern therapeutic options. METHOD: We retrospectively analyzed 142 patients diagnosed with BM from MM at two institutions in Brisbane, Queensland, Australia during 2009-2016. Basic clinico-pathological parameters, treatments used and mortality data were collected...
June 22, 2018: Asia-Pacific Journal of Clinical Oncology
Eunae Kim, Cheolhee Kim
Rational drug design is accomplished through the complementary use of structural biology and computational biology of biological macromolecules involved in disease pathology. Most of the known theoretical approaches for drug design are based on knowledge of the biological targets to which the drug binds. This approach can be used to design drug molecules that restore the balance of the signaling pathway by inhibiting or stimulating biological targets by molecular modeling procedures as well as by molecular dynamics simulations...
June 22, 2018: Current Medicinal Chemistry
Megha Agarwal, Nidhi Thareja, Melody Benjamin, Andre Akhondi, George D Mitchell
PURPOSE OF REVIEW: The purpose of this paper is to identify commonly used tyrosine kinase inhibitors (TKIs) that are associated with hypertension, primarily, vascular endothelial growth factor (VEGF) signaling pathway (VSP) inhibitors. We review the incidence, mechanism, and strategies for management of TKI-induced HTN. We hope to provide clinicians with guidance on how to manage similar clinical scenarios. RECENT FINDINGS: Many of the newer VSP inhibitors are reviewed here, including cediranib, axitinib, pazopanib, and ponatinib...
June 21, 2018: Current Oncology Reports
Elias Jabbour, Ching-Hon Pui, Hagop Kantarjian
Importance: Remarkable progress has occurred in understanding the pathophysiology and in developing improved personalized therapies in adult acute lymphoblastic leukemia (ALL). Observations: We searched MEDLINE (1990-2018), the American Society of Clinical Oncology, and American Society of Hematology websites (2010-2018). We used the search terms "acute lymphoblastic or lymphocytic leukemia" or "ALL." We largely selected publications in the past 5 years but did not exclude commonly referenced and highly regarded older publications...
June 21, 2018: JAMA Oncology
Shane P Duggan, Catherine Garry, Fiona M Behan, Sinead Phipps, Hiromi Kudo, Murat Kirca, Abdul Zaheer, Sarah McGarrigle, John V Reynolds, Robert Goldin, Steve E Kalloger, David F Schaeffer, Aideen Long, Jessica Strid, Dermot Kelleher
Background & Aims: Effective therapeutic approaches are urgently required to tackle the alarmingly poor survival outcomes in esophageal adenocarcinoma (EAC) patients. EAC originates from within the intestinal-type metaplasia, Barrett's esophagus, a condition arising on a background of gastroesophageal reflux disease and associated inflammation. Methods: This study used a druggable genome small interfering RNA (siRNA) screening library of 6022 siRNAs in conjunction with bioinformatics platforms, genomic studies of EAC tissues, somatic variation data of EAC from The Cancer Genome Atlas data of EAC, and pathologic and functional studies to define novel EAC-associated, and targetable, immune factors...
2018: Cellular and Molecular Gastroenterology and Hepatology
Shinji Nakamichi, Masahiro Seike, Akihiko Miyanaga, Mika Chiba, Fenfei Zou, Akiko Takahashi, Arimi Ishikawa, Shinobu Kunugi, Rintaro Noro, Kaoru Kubota, Akihiko Gemma
Anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) induce a dramatic response in non-small cell lung cancer (NSCLC) patients with the ALK fusion gene. However, acquired resistance to ALK-TKIs remains an inevitable problem. In this study, we aimed to discover novel therapeutic targets to conquer ALK-positive lung cancer. We established three types of ALK-TKI (crizotinib, alectinib and ceritinib)-resistant H2228 NSCLC cell lines by high exposure and stepwise methods. We found these cells showed a loss of ALK signaling, overexpressed AXL with epithelial-mesenchymal transition (EMT), and had cancer stem cell-like (CSC) properties, suggesting drug-tolerant cancer cell subpopulations...
June 5, 2018: Oncotarget
Teresa Morán, Eudald Felip, Joaquim Bosch-Barrera, Itziar de Aguirre, Jose Luis Ramirez, Carles Mesia, Enric Carcereny, Diana Roa, Elia Sais, Yolanda García, Remei Blanco, Silvia Sanchez, Claudia Rosa Villacorta, Cristina Queralt, Jose María Velarde, Rafael Rosell
Background: Osimertinib is efficacious in lung cancer patients with epidermal growth factor receptor ( EGFR ) mutations and acquired resistance (AR) to EGFR tyrosine kinase inhibitors due to EGFR -T790M mutation (T790M). We sought to describe T790M changes in serum/plasma during osimertinib therapy and correlate these changes with treatment outcomes. Material and methods: Serum/plasma from EGFR -mutant lung cancer patients with T790M-AR was collected before and during osimertinib treatment...
June 5, 2018: Oncotarget
Meriem Sarah Mekki, Alexandra Mougel, Audrey Vinchent, Charlotte Paquet, Marie-Christine Copin, Catherine Leroy, Zoulika Kherrouche, Jean-Paul Bonte, Oleg Melnyk, Jérôme Vicogne, David Tulasne
The receptor tyrosine kinase MET and its ligand, the Hepatocyte Growth Factor/Scattor Factor (HGF/SF), are essential to the migration, morphogenesis, and survival of epithelial cells. In addition, dysregulation of MET signaling has been shown to promote tumor progression and invasion in many cancers. Therefore, HGF/SF and MET are major targets for chemotherapies. Improvement of targeted therapies requires a perfect understanding of tumor microenvironment that strongly modifies half-life, bio-accessibility and thus, efficacy of treatments...
June 5, 2018: Oncotarget
Gokhan Yildiz
Hepatocellular carcinoma (HCC) is the most common type of liver cancer and the third-leading cause of malignancy-associated mortality worldwide. HCC cells are highly resistant to chemotherapeutic agents. Therefore, there are currently only two US Food and Drug Administration-approved drugs available for the treatment of HCC. The objective of the present study was to analyze the results of previously published high-throughput drug screening, and in vitro genomic and transcriptomic data from HCC cell lines, and to integrate the obtained results to define the underlying molecular mechanisms of drug sensitivity and resistance in HCC cells...
July 2018: Oncology Letters
Kazuharu Kai, Takayuki Iwamoto, Dongwei Zhang, Li Shen, Yuko Takahashi, Arvind Rao, Alastair Thompson, Subrata Sen, Naoto T Ueno
Inflammatory breast cancer (IBC) is a rare subtype of breast cancer, accounting for 8-10% of breast cancer-associated deaths in the US. Clinical hallmarks of IBC include tumor emboli in lymphatic vessels and E-cadherin overexpression, which supports a type of metastasis referred to as cell cluster-based metastasis, prevalent in IBC. In contrast, we previously reported epithelial-to-mesenchymal transition (EMT)-based progression of IBC, utilizing in vivo xenografts and in vitro Matrigel culture models. To address these two contradictory concepts of IBC metastasis, we used Matrigel culture to induce EMT in a panel of IBC cells...
June 21, 2018: Scientific Reports
Young Kyuen Im, Ouafa Najyb, Simon-Pierre Gravel, Shawn McGuirk, Ryuhjin Ahn, Daina Avizonis, Valérie Chénard, Valerie Sabourin, Jesse Hudson, Tony Pawson, Ivan Topisirovic, Michael N Pollak, Julie St-Pierre, Josie Ursini-Siegel
The ShcA adaptor protein transduces oncogenic signals downstream of receptor tyrosine kinases. We show here that breast tumors engage the ShcA pathway to increase their metabolism. ShcA signaling enhanced glucose catabolism through glycolysis and oxidative phosphorylation, rendering breast cancer cells critically dependent on glucose. ShcA signaling simultaneously increased the metabolic rate and flexibility of breast cancer cells by inducing the PGC-1α transcription factor, a central regulator of mitochondrial metabolism...
June 21, 2018: Cancer Research
Vincenza Caolo, Hanna M Peacock, Bahar Kasaai, Geertje Swennen, Emma Gordon, Lena Claesson-Welsh, Mark J Post, Peter Verhamme, Elizabeth A V Jones
OBJECTIVE: Vascular fusion represents an important mechanism of vessel enlargement during development; however, its significance in postnatal vessel enlargement is still unknown. During fusion, 2 adjoining vessels merge to share 1 larger lumen. The aim of this research was to identify the molecular mechanism responsible for vascular fusion. APPROACH AND RESULTS: We previously showed that both low shear stress and DAPT ( N -[ N -(3,5-difluorophenacetyl)-L-alanyl]- S -phenylglycine t-butyl ester) treatment in the embryo result in a hyperfused vascular plexus and that increasing shear stress levels could prevent DAPT-induced fusion...
June 21, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
Wenyan Wang, Yunxia Cao, Xiao Zhou, Bing Wei, Yu Zhang, Xiaochun Liu
Ovarian cancer is the leading cause of death from gynecological malignancies in women. Diagnosis at the early stage remains challenging and efficient treatment is still highly needed. The development and progression of this cancer is associated with many genetic and epigenetic changes, representing the dysregulation of a highly complex signaling network. Previous studies found that protein-tyrosine phosphatase 1 B (PTP1B) was aberrantly expressed in many types of ovarian cancer cells. The exact role of this protein, however, remains controversial...
June 18, 2018: Biochemical and Biophysical Research Communications
Metta Dulk, Balint Szeder, Gabor Glatz, Balazs Mero, Kitti Koprivanacz, Gyongyi Kudlik, Virag Vas, Szabolcs Sipeki, Anna Cserkaszky, László Radnai, Laszlo Buday
The non-receptor tyrosine kinase Src is a central component of the EGF signaling pathway. Our group recently showed that the Frank-ter Haar syndrome protein Tks4 (tyrosine kinase substrate with four Src homology 3 domains) is also involved in EGF signaling. Here we demonstrate that Tks4 and Src bind directly to each other and elucidate the details of the molecular mechanism of this complex formation. Results of GST pull-down and fluorescence polarization assays show that both a proline-rich SH3 binding motif (PSRPLPDAP, residues: 466-474) and an adjacent phosphotyrosine-containing SH2 binding motif (pYEEI, residues: 508-511) in Tks4 are responsible for Src binding...
June 21, 2018: Biochemistry
Harald Schwalbe, Alix Tröster, Stephanie Heinzlmeir, Benedict-Tilman Berger, Santosh L Gande, Krishna Saxena, Sridhar Sreeramulu, Verena Linhard, Amir H Nasiri, Michael Bolte, Susanne Müller, Bernhard Kuster, Guillaume Médard, Denis Kudlinzki
EPH receptors are transmembrane receptor tyrosine kinases. Their extracellular domains bind specifically to ephrin A/B ligands, and this binding modulates the intracellular kinase activity. EPHs are key players in bidirectional intercellular signaling, controlling cell morphology, adhesion and migration. They are increasingly recognized as cancer drug targets. We analyzed the binding of the Novartis inhibitor NVP-BHG712 (NVP) to EPHA2 and EPHB4. Unexpectedly, all tested commercially available NVP samples turned out to be a regioisomer (NVPiso) of the inhibitor, initially described in a Novartis patent application...
June 21, 2018: ChemMedChem
Mizuho Yamazaki, Masaru Mezawa, Keisuke Noda, Yasunobu Iwai, Sari Matsui, Hideki Takai, Yohei Nakayama, Yorimasa Ogata
One of the major causes of tooth loss is chronic inflammation of the periodontium, the tissues surrounding the tooth. Amelotin (AMTN) is a tooth enamel protein which is expressed in maturation-stage ameloblasts and also in the internal basal lamina of junctional epithelium, a unique epithelial structure attached to the tooth surface which protects against the constant microbiological challenge to the periodontium. Localization of AMTN suggests that its function could be involved in the dentogingival attachment...
June 2018: FEBS Open Bio
Cham Han Lee, Soo Jeong Lee, Sung Ho Choi, Sei Hyun Ahn, Byung Ho Son, Jong Won Lee, Jong Han Yu, Nak-Jung Kwon, Woo Chung Lee, Kap-Seok Yang, Dong Hyoung Lee, Du Yeol Han, Mi So Choi, Pyeong-Soo Park, Hyun Kyung Lee, Myoung Shin Kim, Jinseon Lee, Byung Hee Jeon
Liquid biopsy using circulating tumor cells (CTCs) is a noninvasive and repeatable procedure, and is therefore useful for molecular assays. However, the rarity of CTCs remains a challenge. To overcome this issue, our group developed a novel technology for the isolation of CTCs on the basis of cell size difference. The present study isolated CTCs from patients with breast cancer using this method, and then used these cells for cancer gene panel analysis. Blood samples from eight patients with breast cancer were collected, and CTCs were enriched using size-based filtration...
July 2018: Oncology Letters
Jiukai Wan, Jun Zhang, Junqiang Zhang
The present study aimed to investigate the expression of tumor protein p53 (p53), and its mechanism of function, in prostate cancer (PC). Small interfering RNA (siRNA) was used to interfere with p53 expression in the PC cell line, DU145. Cell viability and p53 expression were analyzed using cell counting kit-8 (CCK-8) and western blotting. The effects of p53 expression on the proliferation, migration and adhesion abilities of PC cells were analyzed using Cell Counting kit-8, Transwell and adhesion assays. Changes in cell proliferation, migration and adhesion ability were observed following treatment with extracellular signal-regulated kinase (ERK) inhibitor, PD184352, and janus kinase (JNK) inhibitor, SP60012...
July 2018: Oncology Letters
Xiuzhi Zhou, Li Cai, Junjie Liu, Xiaomin Hua, Ying Zhang, Huilin Zhao, Bin Wang, Boqing Li, Pengzhou Gai
Epidermal growth factor receptor (EGFR) is an important gene in the development of lung adenocarcinoma. However, there is controversy regarding the association between EGFR mutations and survival time of patients with lung adenocarcinoma. In the present study, tissue specimens and clinical data were collected from 219 patients with lung adenocarcinoma who had not undergone prior radiotherapy or chemotherapy. EGFR mutations were detected using a fluorescence polymerase chain reaction method, and the association between EGFR mutations and clinicopathological characteristics was analyzed...
July 2018: Oncology Letters
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