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Zeng Q, He J, Chen X, Yuan Q, Yin L, Liang Y, Zu X, Shen Y. Recent advances in hematopoietic cell kinase in cancer progression: Mechanisms and inhibitors. Biomed Pharmacother 2024; 176:116932. [PMID: 38870631 DOI: 10.1016/j.biopha.2024.116932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 06/04/2024] [Accepted: 06/09/2024] [Indexed: 06/15/2024] Open
Abstract
Hematopoietic cell kinase (Hck), a non-receptor tyrosine kinase belonging to the Src kinase family, is intricately linked to the pathogenesis of numerous human diseases, with a particularly pronounced association with cancer. Hck not only directly impacts the proliferation, migration, and apoptosis of cancer cells but also interacts with JAK/STAT, MEK/ERK, PI3K/AKT, CXCL12/CXCR4, and other pathways. Hck also influences the tumor microenvironment to facilitate the onset and progression of cancer. This paper delves into the functional role and regulatory mechanisms of Hck in various solid tumors. Additionally, it explores the implications of Hck in hematological malignancies. The review culminates with a summary of the current research status of Hck inhibitors, the majority of which are in the pre-clinical phase of investigation. Notably, these inhibitors are predominantly utilized in the therapeutic management of leukemia, with their combinatorial potential indicating promising avenues for future research. In conclusion, this review underscores the significance of the mechanism of Hck in solid tumors. This insight is crucial for comprehending the current research trends regarding Hck: targeted therapy against Hck shows great promise in both diagnosis and treatment of malignant tumors. Further investigation into the role of Hck in cancer, coupled with the development of specific inhibitors, has the potential to revolutionize approaches to cancer treatment.
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Affiliation(s)
- Qiting Zeng
- Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China; Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hunan Province Clinical Research Center for Accurate Diagnosis and Treatment of High-incidence Sexually Transmitted Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hunan 421001, China
| | - Jun He
- Department of Spine Surgery, The Nanhua Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang 421002, China
| | - Xiguang Chen
- Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Qiong Yuan
- Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China; Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hunan Province Clinical Research Center for Accurate Diagnosis and Treatment of High-incidence Sexually Transmitted Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hunan 421001, China
| | - Liyang Yin
- Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China
| | - Yuxin Liang
- Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China; Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, Hunan Province Clinical Research Center for Accurate Diagnosis and Treatment of High-incidence Sexually Transmitted Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hunan 421001, China
| | - Xuyu Zu
- Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China.
| | - Yingying Shen
- Cancer Research Institute, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China.
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Goel RK, Kim N, Lukong KE. Seeking a better understanding of the non-receptor tyrosine kinase, SRMS. Heliyon 2023; 9:e16421. [PMID: 37251450 PMCID: PMC10220380 DOI: 10.1016/j.heliyon.2023.e16421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 05/14/2023] [Accepted: 05/16/2023] [Indexed: 05/31/2023] Open
Abstract
SRMS (Src-Related kinase lacking C-terminal regulatory tyrosine and N-terminal Myristoylation Sites) is a non-receptor tyrosine kinase first reported in a 1994 screen for genes regulating murine neural precursor cells. SRMS, pronounced "Shrims", lacks the C-terminal regulatory tyrosine critical for the regulation of the enzymatic activity of Src-family kinases (SFKs). Another remarkable characteristic of SRMS is its localization into distinct SRMS cytoplasmic punctae (SCPs) or GREL (Goel Raghuveera-Erique Lukong) bodies, a pattern not observed in the SFKs. This unique subcellular localization of SRMS could dictate its cellular targets, proteome, and potentially, substrates. However, the function of SRMS is still relatively unknown. Further, how is its activity regulated and by what cellular targets? Studies have emerged highlighting the potential role of SRMS in autophagy and in regulating the activation of BRK/PTK6. Potential novel cellular substrates have also been identified, including DOK1, vimentin, Sam68, FBKP51, and OTUB1. Recent studies have also demonstrated the potential role of the kinase in various cancers, including gastric and colorectal cancers and platinum resistance in ovarian cancer. This review discusses the advancements made in SRMS-related biology to date and the path to understanding the cellular and physiological significance of the kinase.
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Affiliation(s)
- Raghuveera Kumar Goel
- Center for Network Systems Biology, Boston University, Boston, MA, USA
- Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA
| | - Nayoung Kim
- Department of Biochemistry, Microbiology, and Immunology, 107 Wiggins Road, Health Sciences Building, University of Saskatchewan, Saskatoon S7N 5E5, Saskatchewan, Canada
| | - Kiven Erique Lukong
- Department of Biochemistry, Microbiology, and Immunology, 107 Wiggins Road, Health Sciences Building, University of Saskatchewan, Saskatoon S7N 5E5, Saskatchewan, Canada
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Wang H, Wang N, Zheng X, Wu L, Fan C, Li X, Ye K, Han S. Circular RNA hsa_circ_0009172 suppresses gastric cancer by regulation of microRNA-485-3p-mediated NTRK3. Cancer Gene Ther 2021; 28:1312-1324. [PMID: 33531648 DOI: 10.1038/s41417-020-00280-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 11/19/2020] [Accepted: 12/01/2020] [Indexed: 01/19/2023]
Abstract
Gastric cancer is the third leading cause of cancer-related death worldwide, with relapse and metastasis being major contributors to the mortality. Circular RNAs (circRNAs) have been at the center of several researches and some circRNAs have been indicated to be involved in gastric cancer as sponges. Nevertheless, the mechanism underlying the function of circRNA remains largely unclear. Therefore, this study was conducted with the main objective of screening the associated circRNA in gastric cancer and exploring its mechanism. Expression of hsa_circRNA_0009172 was validated in gastric cancer tissues and cell lines after the correlation between hsa_circRNA_0009172 and prognosis was determined. Moreover, the binding site between miR-485-3p and hsa_circRNA_0009172 or NTRK3 was verified using dual luciferase assay and RNA pull down. Function-gain and -loss experiments were performed for the purpose of detecting the effect of hsa_circRNA_0009172 in vivo and in vitro as well as its mechanism with microRNA (miRNA)-485-3p and NTRK3 in gastric cancer. The hsa_circRNA_0009172 expression was downregulated in gastric cancer tissues and cell lines, indicating a positive association with patient prognosis. Functionally, hsa_circ_0009172 overexpression inhibited proliferative, invasive and migrative potential of gastric cancer cells as well as epithelial-mesenchymal transition (EMT)-related proteins by sponging miR-485-3p to inhibit NTRK3, while miR-485-3p overexpression could reverse the inhibitory effect of hsa_circ_0009172 on gastric cancer. Furthermore, either up-regulation of hsa_circ_0009172 or down-regulation of miR-485-3p led to the suppression of xenograft tumor growth in nude mice. In conclusion, hsa_circ_0009172 serves as a tumor suppressor in gastric cancer by targeting miR-485-3p/NTRK3 axis.
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Affiliation(s)
- Hao Wang
- Department of Oncology, The First Affiliated Hospital, College of Medicine Xi'an Jiaotong University, Xi'an, 710061, PR China
- Department of Radiation Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, 450000, PR China
| | - Nan Wang
- Department of Radiation Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, 450000, PR China
| | - Xiaoli Zheng
- Department of Radiation Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, 450000, PR China
| | - Lei Wu
- Centers of Radiotherapy Oncology, Shaanxi Provincial Tumor Hospital, Xi'an, 710068, PR China
| | - Chengcheng Fan
- Department of Radiation Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, 450000, PR China
| | - Xue Li
- Department of Radiation Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, 450000, PR China
| | - Ke Ye
- Department of Radiation Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, 450000, PR China
| | - Suxia Han
- Department of Oncology, The First Affiliated Hospital, College of Medicine Xi'an Jiaotong University, Xi'an, 710061, PR China.
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Zhu X, Zhang Y, Bai Y, Gu X, Chen G, Sun L, Wang Y, Qiao X, Ma Q, Zhu T, Bu J, Xue J, Liu C. HCK can serve as novel prognostic biomarker and therapeutic target for Breast Cancer patients. Int J Med Sci 2020; 17:2773-2789. [PMID: 33162805 PMCID: PMC7645343 DOI: 10.7150/ijms.43161] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Accepted: 09/16/2020] [Indexed: 01/10/2023] Open
Abstract
The role of HCK expression in the prognosis of breast cancer patients is unclear. Thus, this study aimed to explore the clinical implications of HCK expression in breast cancer. We assessed HCK expression and genetic variations in breast cancer using Oncomine, GEPIA, UALCAN, and cBioPortal databases. Then, immunochemistry was used to analyze HCK expression in breast cancer specimens, non-cancer tissues and metastatic cancer tissues. Consequently, we evaluated the effect of HCK expression on survival outcomes set as disease-free survival (DFS) and overall survival (OS). Finally, STRING, Coexpedia, and TISIDB database were explored to identify the molecular functions and regulation pathways of HCK. We found that breast cancer tissues have more HCK mRNA transcripts than non-cancer tissues. Patients with HCK expression had significantly shorter DFS and OS. The ratio of HCK expression was higher in cancer tissues than in non-cancer tissues. These results from STRING database, FunRich software, and TISIDB database showed that HCK was involved in mediating multiple biological processes including immune response-regulating signaling pathway, cell growth and maintenance through multiple signaling pathways including epithelial to mesenchymal transition, PI3K/AKT signaling pathway, and focal adhesion. Overall, HCK may be an oncogene in the development of breast cancer and thus may as a novel biomarker and therapeutic target for breast cancer.
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MESH Headings
- Aged
- Antineoplastic Agents/pharmacology
- Antineoplastic Agents/therapeutic use
- Biomarkers, Tumor/antagonists & inhibitors
- Biomarkers, Tumor/blood
- Biomarkers, Tumor/genetics
- Breast/pathology
- Breast/surgery
- Breast Neoplasms/blood
- Breast Neoplasms/diagnosis
- Breast Neoplasms/mortality
- Breast Neoplasms/therapy
- Carcinoma, Ductal, Breast/blood
- Carcinoma, Ductal, Breast/diagnosis
- Carcinoma, Ductal, Breast/mortality
- Carcinoma, Ductal, Breast/therapy
- Cell Line, Tumor
- Chemotherapy, Adjuvant/methods
- Disease-Free Survival
- Epithelial-Mesenchymal Transition/drug effects
- Epithelial-Mesenchymal Transition/genetics
- Female
- Focal Adhesions/drug effects
- Focal Adhesions/genetics
- Gene Expression Regulation, Neoplastic
- Humans
- Immunochemistry
- Mastectomy
- Middle Aged
- Molecular Targeted Therapy/methods
- Neoplasm Recurrence, Local/epidemiology
- Neoplasm Recurrence, Local/genetics
- Neoplasm Recurrence, Local/pathology
- Phosphatidylinositol 3-Kinases
- Prognosis
- Proto-Oncogene Proteins c-akt/metabolism
- Proto-Oncogene Proteins c-hck/antagonists & inhibitors
- Proto-Oncogene Proteins c-hck/blood
- Proto-Oncogene Proteins c-hck/genetics
- Risk Assessment/methods
- Signal Transduction/drug effects
- Signal Transduction/genetics
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Affiliation(s)
- Xudong Zhu
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, 110004, China
| | - Yixiao Zhang
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, 110004, China
| | - Yang Bai
- Department of Operating Room, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, 110004, China
| | - Xi Gu
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, 110004, China
| | - Guanglei Chen
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, 110004, China
| | - Lisha Sun
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, 110004, China
| | - Yulun Wang
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, 110004, China
| | - Xinbo Qiao
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, 110004, China
| | - Qingtian Ma
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, 110004, China
| | - Tong Zhu
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, 110004, China
| | - Jiawen Bu
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, 110004, China
| | - Jinqi Xue
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, 110004, China
| | - Caigang Liu
- Department of Oncology, Shengjing Hospital of China Medical University, Shenyang, Liaoning Province, 110004, China
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Identification of the SRC-family tyrosine kinase HCK as a therapeutic target in mantle cell lymphoma. Leukemia 2020; 35:881-886. [PMID: 32591642 PMCID: PMC7932922 DOI: 10.1038/s41375-020-0934-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 05/18/2020] [Accepted: 06/16/2020] [Indexed: 01/20/2023]
Abstract
Mantle cell lymphoma (MCL) is an aggressive non-Hodgkin lymphoma subtype arising from naïve B cells. Although novel therapeutics have improved patient prognosis, drug resistance remains a key problem. Here, we show that the SRC-family tyrosine kinase hematopoietic cell kinase (HCK), which is primarily expressed in the hematopoietic lineage but not in mature B cells, is aberrantly expressed in MCL, and that high expression of HCK is associated with inferior prognosis of MCL patients. HCK expression is controlled by the toll-like receptor (TLR) adaptor protein MYD88 and can be enhanced by TLR agonists in MCL cell lines and primary MCL. In line with this, primary MCL with high HCK expression are enriched for a TLR-signaling pathway gene set. Silencing of HCK expression results in cell cycle arrest and apoptosis. Furthermore, HCK controls integrin-mediated adhesion of MCL cells to extracellular matrix and stromal cells. Taken together, our data indicate that TLR/MYD88-controlled aberrant expression of HCK plays a critical role in MCL proliferation and survival as well as in retention of the malignant cells in the growth- and survival-supporting lymphoid organ microenvironment, thereby contributing to lymphomagenesis. These novel insights provide a strong rationale for therapeutic targeting of HCK in MCL.
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Matsuura VKSK, Yoshida CA, Komori H, Sakane C, Yamana K, Jiang Q, Komori T. Expression of a Constitutively Active Form of Hck in Chondrocytes Activates Wnt and Hedgehog Signaling Pathways, and Induces Chondrocyte Proliferation in Mice. Int J Mol Sci 2020; 21:E2682. [PMID: 32290615 PMCID: PMC7215647 DOI: 10.3390/ijms21082682] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 03/30/2020] [Accepted: 04/09/2020] [Indexed: 12/30/2022] Open
Abstract
Runx2 is required for chondrocyte proliferation and maturation. In the search of Runx2 target genes in chondrocytes, we found that Runx2 up-regulated the expression of hematopoietic cell kinase (Hck), which is a member of the Src tyrosine kinase family, in chondrocytes, that Hck expression was high in cartilaginous limb skeletons of wild-type mice but low in those of Runx2-/- mice, and that Runx2 bound the promoter region of Hck. To investigate the functions of Hck in chondrocytes, transgenic mice expressing a constitutively active form of Hck (HckCA) were generated using the Col2a1 promoter/enhancer. The hind limb skeletons were fused, the tibia became a large, round mass, and the growth plate was markedly disorganized. Chondrocyte maturation was delayed until E16.5 but accelerated thereafter. BrdU-labeled, but not terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive, chondrocytes were increased. Furthermore, Hck knock-down reduced the proliferation of primary chondrocytes. In microarray and real-time RT-PCR analyses using hind limb RNA from HckCA transgenic mice, the expression of Wnt (Wnt10b, Tcf7, Lef1, Dkk1) and hedgehog (Ihh, Ptch1, and Gli1) signaling pathway genes was upregulated. These findings indicated that Hck, whose expression is regulated by Runx2, is highly expressed in chondrocytes, and that HckCA activates Wnt and hedgehog signaling pathways, and promotes chondrocyte proliferation without increasing apoptosis.
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Affiliation(s)
- Viviane K. S. Kawata Matsuura
- Basic and Translational Research Center for Hard Tissue Disease, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8588, Japan
| | - Carolina Andrea Yoshida
- Basic and Translational Research Center for Hard Tissue Disease, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8588, Japan
| | - Hisato Komori
- Basic and Translational Research Center for Hard Tissue Disease, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8588, Japan
| | - Chiharu Sakane
- Division of Comparative Medicine, Life Science Support Center, Nagasaki University, Nagasaki 852-8523, Japan
| | - Kei Yamana
- Teijin Institute for Bio-Medical Research, TEIJIN LIMITED, Tokyo 100-8585, Japan
| | - Qing Jiang
- Basic and Translational Research Center for Hard Tissue Disease, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8588, Japan
| | - Toshihisa Komori
- Basic and Translational Research Center for Hard Tissue Disease, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8588, Japan
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Pan X, Wang Y, Li C, Zhou Z, Zhong Y, Feng J, Lu J. Exon Coverage Variations Between Cancer Tissues and Adjacent Non-Cancerous Tissues are Prognostic Factors in Gastric Cancer. Onco Targets Ther 2020; 13:61-70. [PMID: 32021255 PMCID: PMC6956395 DOI: 10.2147/ott.s234351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Accepted: 12/02/2019] [Indexed: 11/23/2022] Open
Abstract
Introduction Gastric cancer is highly heterogeneous both clinically and pathologically and is one of the leading causes of cancer-related deaths worldwide. Genomic coverage variations, also known as copy number variations (CNVs), play a critical role in the carcinogenesis of gastric cancer. Many studies have demonstrated that DNA CNVs are important factors affecting the expression of protein-encoding genes in the gastric cancer genome. Methods Thirty gastric cancer patients from a Chinese population were enrolled. Genomic DNA was extracted from gastric cancer tissue and matched adjacent non-cancerous tissue from each patient. A panel of 1,021 genes including 3300 exons was designed and subjected to next-generation sequencing. Copy numbers of each gene and exon were calculated for each tissue. Coverage variations between gastric cancer tissue and matched adjacent non-cancerous tissue were also calculated, and we examined the correlation between overall survival of patients and coverage variation type for each exon. Results DNA from cancerous tissue and corresponding adjacent non-cancerous tissue were significantly different with respect to the pattern of gene copy number. Exon copy numbers were highly consistent among non-cancerous samples and confirmed that non-cancerous tissue contain diploid genomes. In contrast, the gene coverage pattern among cancerous tissue showed significant differences and confirmed that gastric cancer is a genetically heterogeneous disease. Numerous exon coverage variations were identified in gastric cancer tissue compared with matched, adjacent non-cancerous tissue. Overall survival between patients with and without coverage variations in regions of NOTCH2, NTRK3, ERBB2 and RERE exons exhibited significant differences. This is consistent with previous reports and indicates that these findings may have prognostic value. Conclusion Our results confirm that gastric cancer is a genetically heterogeneous disease. Exon coverage variations between cancer tissue and their adjacent non-cancerous tissue were shown to be associated with prognosis in gastric cancer.
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Affiliation(s)
- Xuan Pan
- Department of Medical Oncology, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, Jiangsu 210009, People's Republic of China
| | - Yajing Wang
- Department of Medical Oncology, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, Jiangsu 210009, People's Republic of China
| | - Chenchen Li
- Department of Medical Oncology, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, Jiangsu 210009, People's Republic of China
| | - Zhaofei Zhou
- Department of Medical Oncology, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, Jiangsu 210009, People's Republic of China
| | - Yuejiao Zhong
- Department of Medical Oncology, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, Jiangsu 210009, People's Republic of China
| | - Jifeng Feng
- Department of Medical Oncology, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, Jiangsu 210009, People's Republic of China
| | - Jianwei Lu
- Department of Medical Oncology, The Affiliated Cancer Hospital of Nanjing Medical University, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing, Jiangsu 210009, People's Republic of China
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Poh AR, Dwyer AR, Eissmann MF, Chand AL, Baloyan D, Boon L, Murrey MW, Whitehead L, O'Brien M, Lowell CA, Putoczki TL, Pixley FJ, O'Donoghue RJJ, Ernst M. Inhibition of the SRC Kinase HCK Impairs STAT3-Dependent Gastric Tumor Growth in Mice. Cancer Immunol Res 2020; 8:428-435. [PMID: 31992566 DOI: 10.1158/2326-6066.cir-19-0623] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Revised: 12/08/2019] [Accepted: 01/24/2020] [Indexed: 01/25/2023]
Abstract
Persistent activation of the latent transcription factor STAT3 is observed in gastric tumor epithelial and immune cells and is associated with a poor patient prognosis. Although targeting STAT3-activating upstream kinases offers therapeutically viable targets with limited specificity, direct inhibition of STAT3 remains challenging. Here we provide functional evidence that myeloid-specific hematopoietic cell kinase (HCK) activity can drive STAT3-dependent epithelial tumor growth in mice and is associated with alternative macrophage activation alongside matrix remodeling and tumor cell invasion. Accordingly, genetic reduction of HCK expression in bone marrow-derived cells or systemic pharmacologic inhibition of HCK activity suppresses alternative macrophage polarization and epithelial STAT3 activation, and impairs tumor growth. These data validate HCK as a molecular target for the treatment of human solid tumors harboring excessive STAT3 activity.
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Affiliation(s)
- Ashleigh R Poh
- Olivia Newton-John Cancer Research Institute and La Trobe University School of Cancer Medicine, Victoria, Australia
| | - Amy R Dwyer
- Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
| | - Moritz F Eissmann
- Olivia Newton-John Cancer Research Institute and La Trobe University School of Cancer Medicine, Victoria, Australia
| | - Ashwini L Chand
- Olivia Newton-John Cancer Research Institute and La Trobe University School of Cancer Medicine, Victoria, Australia
| | - David Baloyan
- Olivia Newton-John Cancer Research Institute and La Trobe University School of Cancer Medicine, Victoria, Australia
| | | | - Michael W Murrey
- School of Medicine and Pharmacology, The University of Western Australia, Western Australia, Australia
| | - Lachlan Whitehead
- The Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology, University of Melbourne, Victoria, Australia
| | - Megan O'Brien
- Olivia Newton-John Cancer Research Institute and La Trobe University School of Cancer Medicine, Victoria, Australia
| | | | - Tracy L Putoczki
- The Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology, University of Melbourne, Victoria, Australia
| | - Fiona J Pixley
- School of Medicine and Pharmacology, The University of Western Australia, Western Australia, Australia
| | - Robert J J O'Donoghue
- Department of Pharmacology and Therapeutics, University of Melbourne, Victoria, Australia
| | - Matthias Ernst
- Olivia Newton-John Cancer Research Institute and La Trobe University School of Cancer Medicine, Victoria, Australia.
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Roles of TrkC Signaling in the Regulation of Tumorigenicity and Metastasis of Cancer. Cancers (Basel) 2020; 12:cancers12010147. [PMID: 31936239 PMCID: PMC7016819 DOI: 10.3390/cancers12010147] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 01/02/2020] [Accepted: 01/07/2020] [Indexed: 12/12/2022] Open
Abstract
Tropomyosin receptor kinase (Trk) C contributes to the clinicopathology of a variety of human cancers, and new chimeric oncoproteins containing the tyrosine kinase domain of TrkC occur after fusion to the partner genes. Overexpression of TrkC and TrkC fusion proteins was observed in patients with a variety of cancers, including mesenchymal, hematopoietic, and those of epithelial cell lineage. Both microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) were involved in the regulation of TrkC expression through transcriptional and posttranscriptional alteration. Aberrant activation of TrkC and TrkC fusion proteins markedly induces the epithelial-mesenchymal transition (EMT) program, growth rate, tumorigenic capacity via constitutive activation of Ras-MAP kinase (MAPK), PI3K-AKT, and the JAK2-STAT3 pathway. The clinical trial of TrkC or TrkC fusion-positive cancers with newly developed Trk inhibitors demonstrated that Trk inhibitors were highly effective in inducing tumor regression in patients who do not harbor mutations in the kinase domain. Recently, there has been a progressive accumulation of mutations in TrkC or the TrkC fusion protein detected in the clinic and its related cancer cell lines caused by high-throughput DNA sequencing. Despite given the high overall response rate against Trk or Trk fusion proteins-positive solid tumors, acquired drug resistance was observed in patients with various cancers caused by mutations in the Trk kinase domain. To overcome acquired resistance caused by kinase domain mutation, next-generation Trk inhibitors have been developed, and these inhibitors are currently under investigation in clinical trials.
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Yang M, Hlady RA, Zhou D, Ho TH, Robertson KD. In silico DNA methylation analysis identifies potential prognostic biomarkers in type 2 papillary renal cell carcinoma. Cancer Med 2019; 8:5760-5768. [PMID: 31361072 PMCID: PMC6745825 DOI: 10.1002/cam4.2402] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Revised: 06/10/2019] [Accepted: 06/21/2019] [Indexed: 12/27/2022] Open
Abstract
There are currently no effective treatments for advanced‐stage papillary renal cell carcinoma (PRCC). The goal of this study is to define potential DNA methylation‐based markers and treatment targets for advanced‐stage type 2 PRCC. Progressive DNA methylation changes and copy number variation (CNV) from localized to advanced‐stage type 2 PRCC are analyzed by using methylation data generated by TCGA's kidney renal papillary cell carcinoma (TCGA‐KIRP, 450k array) project. Survival analyses are performed for the identified biomarkers and genes with CNV. In addition, expression of the corresponding genes is investigated by RNA‐seq analysis. Progressive methylation changes in several CpGs from localized to advanced‐stage type 2 PRCC are observed. Four CpGs (cg00489401, cg27649239, cg20555674, and cg07196505) in particular are identified as markers for differentiating between localized and advanced‐stage type 2 PRCC. Copy number analysis reveals that copy gain of PTK7 mostly occurs in advanced‐stage type 2 PRCC. Both the four CpG methylation changes and PTK7 copy number gain are associated with patient survival. RNA‐seq analysis demonstrates that PTK7 copy gain leads to higher PTK7 expression relative to tumors without copy number gain. Moreover, PTK7 is significantly upregulated from localized to advanced‐stage type 2 PRCC and is linked to cancer cell invasion. In conclusion, DNA methylation markers that differentiate between localized and advanced‐stage type 2 PRCC may serve as useful markers for disease staging or outcome, while PTK7 copy gain represents a potential treatment target for advanced‐stage type 2 PRCC. Stepwise methylation changes and copy number gain also associate with disease stage in PRCC patients.
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Affiliation(s)
- Man Yang
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota.,Department of Nephrology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Ryan A Hlady
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota
| | - Dan Zhou
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota
| | - Thai H Ho
- Division of Hematology and Medical Oncology, Mayo Clinic, Scottsdale, Arizona
| | - Keith D Robertson
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota
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11
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Li Y, Han X, Xu W, Rao Z, Li X. Purification and characterization of the extracellular region of human receptor tyrosine kinase like orphan receptor 2 (ROR2). Protein Expr Purif 2019; 158:74-80. [PMID: 30826310 DOI: 10.1016/j.pep.2019.02.015] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Revised: 02/25/2019] [Accepted: 02/25/2019] [Indexed: 11/25/2022]
Abstract
Receptor tyrosine kinase like orphan receptor 2 (ROR2) is a co-receptor for some Wnt proteins including Wnt5a that activate the noncanonical Wnt/planar cell polarity (PCP) signaling pathway. Upregulation of ROR2 is associated with several cancer forms. The extracellular region of ROR2, which contains an immunoglobulin (Ig)-like domain, a Frizzled like cysteine-rich domain (CRD) and a Kringle domain, is a potential anticancer drug target. The structural and biochemical properties of the ROR2 extracellular region remain largely unexplored. Here we describe the mapping and purification, using a baculovirus - insect cell system, of a near-full-length ROR2 extracellular fragment (residues 53-402), which is well-behaved and suitable for future structural and biochemical analysis. We show that the extracellular region of ROR2 per se is monomeric in solution. Different monoclonal antibodies raised against the purified ROR2 protein can specifically recognize the protein and can either inhibit or activate the PCP activity in a cell-based assay, and are thus potentially useful for future mechanistic and therapeutic/diagnostic studies. The biological relevance of these antibodies further demonstrates that the purified recombinant ROR2 protein is properly folded and biochemically active.
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Affiliation(s)
- Yuan Li
- Collage of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Xu Han
- Collage of Life Sciences, Nankai University, Tianjin, 300071, China
| | - Wenqing Xu
- Department of Biological Structure, University of Washington, Seattle, WA, 98195, USA.
| | - Zihe Rao
- Collage of Life Sciences, Nankai University, Tianjin, 300071, China.
| | - Xin Li
- Collage of Life Sciences, Nankai University, Tianjin, 300071, China.
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12
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Mafficini A, Amato E, Cataldo I, Rusev BC, Bertoncello L, Corbo V, Simbolo M, Luchini C, Fassan M, Cantù C, Salvia R, Marchegiani G, Tortora G, Lawlor RT, Bassi C, Scarpa A. Ampulla of Vater Carcinoma: Sequencing Analysis Identifies TP53 Status as a Novel Independent Prognostic Factor and Potentially Actionable ERBB, PI3K, and WNT Pathways Gene Mutations. Ann Surg 2018; 267:149-156. [PMID: 27611608 DOI: 10.1097/sla.0000000000001999] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
OBJECTIVE To identify molecular prognostic factors and potentially actionable mutations in ampulla of Vater cancer (AVC). BACKGROUND The largely variable outcomes of AVCs make clinical decisions difficult regarding the need of postsurgical therapy, which is based on morphological and immunohistochemical classification that do not adequately consider the varying degrees of heterogeneity present in many AVCs. No approved targeted therapies for AVC exist, but some show promising results requiring better molecular characterization to identify potential responders. METHODS We assessed 80 AVCs for the prognostic value of mutations of kirsten rat sarcoma (KRAS), neuroblastoma RAS (NRAS), B rapidly accelerated fibrosarcoma (BRAF), TP53, and 4 membrane erythroblastosis oncogene B (ERBB) receptor tyrosine kinases (EGFR-ERBB1, HER2-ERBB2, HER3-ERBB3, HER4-ERBB4) amenable to pharmacological inhibition. Moreover, we evaluated mutations in 16 key components of rat sarcoma (RAS), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), protein 53 (P53), transforming growth factor beta (TGF-β), and wingless/integrated (WNT) pathways, recently associated to AVC by whole-exome sequencing. RESULTS TP53 and KRAS were mutated in 41% and 35% of cases, respectively, and emerged as independent prognostic factors together with tumor stage and regardless of the histotype (TP53: P = 0.0006; KRAS: P = 0.0018; stage IIB: P = 0.0117; stage III-IV: P = 0.0020). ERBB, WNT and PI3K pathway genes were mutated in 37.5% of cases. CONCLUSIONS KRAS and TP53 mutations are negative predictors of survival in AVCs, regardless of histotype. Potentially actionable mutations in ERBB, WNT, and PI3K signaling pathway genes are present in 37.5% of all cases. These might be amenable to target therapy using available drugs like Everolimus in PI3K-mutated cases or compounds under active screening against ERBB and WNT signaling.
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Affiliation(s)
| | - Eliana Amato
- ARC-NET Research Centre, University of Verona, Verona, Italy
| | - Ivana Cataldo
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy
| | | | - Luca Bertoncello
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy
| | - Vincenzo Corbo
- ARC-NET Research Centre, University of Verona, Verona, Italy
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy
| | - Michele Simbolo
- ARC-NET Research Centre, University of Verona, Verona, Italy
| | - Claudio Luchini
- ARC-NET Research Centre, University of Verona, Verona, Italy
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy
| | - Matteo Fassan
- ARC-NET Research Centre, University of Verona, Verona, Italy
| | - Cinzia Cantù
- ARC-NET Research Centre, University of Verona, Verona, Italy
| | - Roberto Salvia
- Department of Surgery, Istituto del Pancreas, University of Verona, Verona, Italy
| | - Giovanni Marchegiani
- Department of Surgery, Istituto del Pancreas, University of Verona, Verona, Italy
| | | | - Rita T Lawlor
- ARC-NET Research Centre, University of Verona, Verona, Italy
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy
| | - Claudio Bassi
- Department of Surgery, Istituto del Pancreas, University of Verona, Verona, Italy
| | - Aldo Scarpa
- ARC-NET Research Centre, University of Verona, Verona, Italy
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy
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13
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Zhu D, Yang Z, Liu Z, Zou Q, Yuan Y, Hu C. Association between Wnt inhibitory factor 1 and receptor tyrosine kinase-like orphan receptor 2 protein expression and the clinical pathological significance in benign and malignant pancreatic lesions. Oncol Lett 2017; 13:2244-2252. [PMID: 28454387 PMCID: PMC5403277 DOI: 10.3892/ol.2017.5704] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2016] [Accepted: 11/25/2016] [Indexed: 11/30/2022] Open
Abstract
Pancreatic cancer is one of the most malignant types of tumor. It is important to elucidate the underlying molecular mechanisms of pancreatic tumorigenesis and to identify novel biomarkers as therapeutic targets of pancreatic cancer. In the present study, the protein expression levels of Wnt inhibitory factor 1 (WIF1) and receptor tyrosine kinase-like orphan receptor 2 (ROR2) were examined in a collection of pancreatic ductal carcinoma and benign pancreatic lesion tissue samples using immunohistochemistry. The positive expression rate of WIF1 protein in pancreatic ductal carcinoma was demonstrated to be significantly decreased compared with that of the paracancerous tissue, benign lesions and wild-type pancreatic tissue (P=0.002, P<0.0001, P=0.001, respectively). The positive expression rate of ROR2 protein in pancreatic ductal carcinoma was demonstrated to be significantly increased compared with that of the paracancerous tissue, benign lesions and wild-type pancreatic tissue (P<0.0001). There was a negative association between WIF1 and ROR2 expression in the pancreatic ductal carcinoma samples (P=0.004). The survival period of patients with negative WIF1 and positive ROR2 protein expression was demonstrated to be significantly decreased compared with that of patients with positive WIF1 and negative ROR2 protein expression (P<0.0001). The expression levels of WIF1 and ROR2 protein reflected the incidence, development, clinical and biological behavior, and prognosis of pancreatic ductal carcinoma. Patients with negative WIF1 and positive ROR2 protein expression had poor prognosis. The results indicate that WIF1 and ROR2 are important biomarkers in pancreatic cancer.
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Affiliation(s)
- Daoqi Zhu
- Department of Oncology, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China.,Department of Oncology, No. 163 Central Hospital of Chinese People's Liberation Army, Changsha, Hunan 410003, P.R. China
| | - Zhulin Yang
- Research Laboratory of Hepatobiliary Diseases, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Ziru Liu
- Research Laboratory of Hepatobiliary Diseases, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
| | - Qiong Zou
- Department of Pathology, Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
| | - Yuan Yuan
- Department of Pathology, Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
| | - Chunhong Hu
- Department of Oncology, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, P.R. China
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14
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Wu ZC, Xiong L, Wang LX, Miao XY, Liu ZR, Li DQ, Zou Q, Liu KJ, Zhao H, Yang ZL. Comparative study of ROR2 and WNT5a expression in squamous/adenosquamous carcinoma and adenocarcinoma of the gallbladder. World J Gastroenterol 2017; 23:2601-2612. [PMID: 28465645 PMCID: PMC5394524 DOI: 10.3748/wjg.v23.i14.2601] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Revised: 02/01/2017] [Accepted: 03/02/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the expression and clinical pathological significance of ROR2 and WNT5a in gallbladder squamous/adenosquamous carcinoma (SC/ASC) and adenocarcinoma (AC). METHODS EnVision immunohistochemistry was used to stain for ROR2 and WNT5a in 46 SC/ASC patients and 80 AC patients. RESULTS Poorly differentiated AC among AC patients aged > 45 years were significantly more frequent compared with SC/ASC patients, while tumors with a maximal diameter > 3 cm in the SC/ASC group were significantly more frequent compared with the AC group. Positive ROR2 and WNT5a expression was significantly lower in SC/ASC or AC with a maximal mass diameter ≤ 3 cm, a TNM stage of I + II, no lymph node metastasis, no surrounding invasion, and radical resection than in patients with a maximal mass diameter > 3 cm, TNM stage IV, lymph node metastasis, surrounding invasion, and no resection. Positive ROR2 expression in patients with highly differentiated SC/ASC was significantly lower than in patients with poorly differentiated SC/ASC. Positive ROR2 and WNT5a expression levels in highly differentiated AC were significantly lower than in poorly differentiated AC. Kaplan-Meier survival analysis showed that differentiation degree, maximal mass diameter, TNM stage, lymph node metastasis, surrounding invasion, surgical procedure and the ROR2 and WNT5a expression levels were closely related to average survival of SC/ASC or AC. The survival of SC/ASC or AC patients with positive expression of ROR2 and WNT5a was significantly shorter than that of patients with negative expression results. Cox multivariate analysis revealed that poor differentiation, a maximal diameter of the mass ≥ 3 cm, TNM stage III or IV, lymph node metastasis, surrounding invasion, unresected surgery and positive ROR2 or WNT5a expression in the SC/ASC or AC patients were negatively correlated with the postoperative survival rate and positively correlated with mortality, which are risk factors and independent prognostic predictors. CONCLUSION SC/ASC or AC patients with positive ROR2 or WNT5a expression generally have a poor prognosis.
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15
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Poh AR, Love CG, Masson F, Preaudet A, Tsui C, Whitehead L, Monard S, Khakham Y, Burstroem L, Lessene G, Sieber O, Lowell C, Putoczki TL, O'Donoghue RJJ, Ernst M. Inhibition of Hematopoietic Cell Kinase Activity Suppresses Myeloid Cell-Mediated Colon Cancer Progression. Cancer Cell 2017; 31:563-575.e5. [PMID: 28399411 PMCID: PMC5479329 DOI: 10.1016/j.ccell.2017.03.006] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Revised: 01/08/2017] [Accepted: 03/16/2017] [Indexed: 12/17/2022]
Abstract
Aberrant activation of the SRC family kinase hematopoietic cell kinase (HCK) triggers hematological malignancies as a tumor cell-intrinsic oncogene. Here we find that high HCK levels correlate with reduced survival of colorectal cancer patients. Likewise, increased Hck activity in mice promotes the growth of endogenous colonic malignancies and of human colorectal cancer cell xenografts. Furthermore, tumor-associated macrophages of the corresponding tumors show a pronounced alternatively activated endotype, which occurs independently of mature lymphocytes or of Stat6-dependent Th2 cytokine signaling. Accordingly, pharmacological inhibition or genetic reduction of Hck activity suppresses alternative activation of tumor-associated macrophages and the growth of colon cancer xenografts. Thus, Hck may serve as a promising therapeutic target for solid malignancies.
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Affiliation(s)
- Ashleigh R Poh
- Olivia Newton-John Cancer Research Institute, La Trobe University School of Cancer Medicine, Heidelberg, VIC 3084, Australia; The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia
| | - Christopher G Love
- The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia
| | - Frederick Masson
- Olivia Newton-John Cancer Research Institute, La Trobe University School of Cancer Medicine, Heidelberg, VIC 3084, Australia
| | - Adele Preaudet
- The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia
| | - Cary Tsui
- The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia
| | - Lachlan Whitehead
- The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia
| | - Simon Monard
- The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia
| | - Yelena Khakham
- The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia
| | - Lotta Burstroem
- The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia
| | - Guillaume Lessene
- The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia; Department of Pharmacology and Therapeutics, University of Melbourne, Melbourne, VIC 3010, Australia
| | - Oliver Sieber
- The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia; Department of Colorectal Surgery, Royal Melbourne Hospital, Melbourne, VIC 3050, Australia; School of Biomedical Sciences, Monash University, Clayton, VIC 3800, Australia
| | - Clifford Lowell
- Department of Pathology and Laboratory Medicine, University of California, San Francisco, CA 94143, USA
| | - Tracy L Putoczki
- Olivia Newton-John Cancer Research Institute, La Trobe University School of Cancer Medicine, Heidelberg, VIC 3084, Australia; The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia
| | - Robert J J O'Donoghue
- Olivia Newton-John Cancer Research Institute, La Trobe University School of Cancer Medicine, Heidelberg, VIC 3084, Australia; The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia.
| | - Matthias Ernst
- Olivia Newton-John Cancer Research Institute, La Trobe University School of Cancer Medicine, Heidelberg, VIC 3084, Australia; The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Melbourne, VIC 3052, Australia.
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16
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Gudernova I, Foldynova-Trantirkova S, Ghannamova BE, Fafilek B, Varecha M, Balek L, Hruba E, Jonatova L, Jelinkova I, Kunova Bosakova M, Trantirek L, Mayer J, Krejci P. One reporter for in-cell activity profiling of majority of protein kinase oncogenes. eLife 2017; 6. [PMID: 28199182 PMCID: PMC5310841 DOI: 10.7554/elife.21536] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Accepted: 01/31/2017] [Indexed: 12/05/2022] Open
Abstract
In-cell profiling enables the evaluation of receptor tyrosine activity in a complex environment of regulatory networks that affect signal initiation, propagation and feedback. We used FGF-receptor signaling to identify EGR1 as a locus that strongly responds to the activation of a majority of the recognized protein kinase oncogenes, including 30 receptor tyrosine kinases and 154 of their disease-associated mutants. The EGR1 promoter was engineered to enhance trans-activation capacity and optimized for simple screening assays with luciferase or fluorescent reporters. The efficacy of the developed, fully synthetic reporters was demonstrated by the identification of novel targets for two clinically used tyrosine kinase inhibitors, nilotinib and osimertinib. A universal reporter system for in-cell protein kinase profiling will facilitate repurposing of existing anti-cancer drugs and identification of novel inhibitors in high-throughput screening studies. DOI:http://dx.doi.org/10.7554/eLife.21536.001
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Affiliation(s)
- Iva Gudernova
- Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | | | | | - Bohumil Fafilek
- Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.,International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic
| | - Miroslav Varecha
- Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.,International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic
| | - Lukas Balek
- Department of Experimental Biology, Faculty of Sciences, Masaryk University, Brno, Czech Republic
| | - Eva Hruba
- Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.,International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic
| | - Lucie Jonatova
- Department of Experimental Biology, Faculty of Sciences, Masaryk University, Brno, Czech Republic
| | - Iva Jelinkova
- Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.,International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic
| | | | - Lukas Trantirek
- Central European Institute of Technology, Masaryk University, Brno, Czech Republic
| | - Jiri Mayer
- Department of Internal Medicine, Hematology and Oncology, Masaryk University Hospital, Brno, Czech Republic
| | - Pavel Krejci
- Department of Biology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.,International Clinical Research Center, St. Anne's University Hospital, Brno, Czech Republic
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17
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Thakur MK, Birudukota S, Swaminathan S, Battula SK, Vadivelu S, Tyagi R, Gosu R. Co-crystal structures of PTK6: With Dasatinib at 2.24 Å, with novel imidazo[1,2-a]pyrazin-8-amine derivative inhibitor at 1.70 Å resolution. Biochem Biophys Res Commun 2016; 482:1289-1295. [PMID: 27993680 DOI: 10.1016/j.bbrc.2016.12.030] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2016] [Accepted: 12/03/2016] [Indexed: 12/29/2022]
Abstract
Human Protein tyrosine kinase 6 (PTK6)(EC:2.7.10.2), also known as the breast tumor kinase (BRK), is an intracellular non-receptor Src-related tyrosine kinase expressed five-fold or more in human breast tumors and breast cancer cell lines but its expression being low or completely absent from normal mammary gland. There is a recent interest in targeting PTK6-positive breast cancer by developing small molecule inhibitor against PTK6. Novel imidazo[1,2-a]pyrazin-8-amines (IPA) derivative compounds and FDA approved drug, Dasatinib are reported to inhibit PTK6 kinase activity with IC50 in nM range. To understand binding mode of these compounds and key interactions that drive the potency against PTK6, one of the IPA compounds and Dasatinib were chosen to study through X-ray crystallography. The recombinant PTK6 kinase domain was purified and co-crystallized at room temperature by the sitting-drop vapor diffusion method, collected X-ray diffraction data at in-house and resolved co-crystal structure of PTK6-KD with Dasatinib at 2.24 Å and with IPA compound at 1.70 Å resolution. Both these structures are in DFG-in & αC-helix-out conformation with unambiguous electron density for Dasatinib or IPA compound bound at the ATP-binding pocket. Relative difference in potency between Dasatinib and IPA compound is delineated through the additional interactions derived from the occupation of additional pocket by Dasatinib at gatekeeper area. Refined crystallographic coordinates for the kinase domain of PTK6 in complex with IPA compound and Dasatinib have been submitted to Protein Data Bank under the accession number 5DA3 and 5H2U respectively.
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Affiliation(s)
- Manish Kumar Thakur
- Department of Biochemistry, University of Mysore, Mysore, 570005, India; Department of Structural Biology, Jubilant Biosys Ltd, Bangalore, 560022, India
| | | | | | | | - Sarvanan Vadivelu
- Department of Structural Biology, Jubilant Biosys Ltd, Bangalore, 560022, India
| | - Rajiv Tyagi
- Department of Structural Biology, Jubilant Biosys Ltd, Bangalore, 560022, India
| | - Ramachandraiah Gosu
- Department of Biochemistry, University of Mysore, Mysore, 570005, India; Department of Structural Biology, Jubilant Biosys Ltd, Bangalore, 560022, India.
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18
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Kneissl J, Hartmann A, Pfarr N, Erlmeier F, Lorber T, Keller S, Zwingenberger G, Weichert W, Luber B. Influence of the HER receptor ligand system on sensitivity to cetuximab and trastuzumab in gastric cancer cell lines. J Cancer Res Clin Oncol 2016; 143:573-600. [PMID: 27933395 PMCID: PMC5352771 DOI: 10.1007/s00432-016-2308-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2016] [Accepted: 11/17/2016] [Indexed: 12/18/2022]
Abstract
Purpose Gastric cancer remains a major health concern, and improvement of the therapeutic options is crucial. Treatment with targeted therapeutics such as the EGFR-targeting antibody cetuximab or the HER2-targeting antibody trastuzumab is either ineffective or moderately effective in this disease, respectively. In this study, we analysed the involvement of the HER receptor ligands amphiregulin (AREG), epidermal growth factor (EGF), heparin-binding epidermal growth factor (HB-EGF) and transforming growth factor alpha (TGFα) in the responsiveness of gastric cancer cell lines to cetuximab and trastuzumab. Methods A panel of 11 gastric cancer cell lines was characterized for cetuximab and trastuzumab sensitivity, ligand secretion and expression and activation of the HER receptors using WST-1 cell proliferation assays, ELISAs and Western blot analyses. We further investigated the effects of an exogenous ligand application on the cetuximab and trastuzumab sensitivity. Results We found no correlation between TGFα secretion and the sensitivity to cetuximab or trastuzumab. For AREG, we confirmed previous results indicating that this ligand is a positive predictor of cetuximab sensitivity. Exogenous HB-EGF was effective in rescuing sensitive cell lines from inhibition of cell proliferation by both, cetuximab and trastuzumab. Conclusions Our data indicate that HB-EGF may be a useful marker for the prediction of trastuzumab sensitivity in gastric cancer. Electronic supplementary material The online version of this article (doi:10.1007/s00432-016-2308-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Julia Kneissl
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Klinikum rechts der Isar, Trogerstr. 18, 81675, Munich, Germany
| | - Anja Hartmann
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Klinikum rechts der Isar, Trogerstr. 18, 81675, Munich, Germany
| | - Nicole Pfarr
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Klinikum rechts der Isar, Trogerstr. 18, 81675, Munich, Germany
| | - Franziska Erlmeier
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Klinikum rechts der Isar, Trogerstr. 18, 81675, Munich, Germany
| | - Thomas Lorber
- Institute for Pathology, University Hospital Basel, Schönbeinstrasse 40, 4031, Basel, Switzerland
| | - Simone Keller
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Klinikum rechts der Isar, Trogerstr. 18, 81675, Munich, Germany
| | - Gwen Zwingenberger
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Klinikum rechts der Isar, Trogerstr. 18, 81675, Munich, Germany
| | - Wilko Weichert
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Klinikum rechts der Isar, Trogerstr. 18, 81675, Munich, Germany
| | - Birgit Luber
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Klinikum rechts der Isar, Trogerstr. 18, 81675, Munich, Germany.
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19
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Zuo WJ, Jiang YZ, Wang YJ, Xu XE, Hu X, Liu GY, Wu J, Di GH, Yu KD, Shao ZM. Dual Characteristics of Novel HER2 Kinase Domain Mutations in Response to HER2-Targeted Therapies in Human Breast Cancer. Clin Cancer Res 2016; 22:4859-4869. [DOI: 10.1158/1078-0432.ccr-15-3036] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Accepted: 05/02/2016] [Indexed: 11/16/2022]
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Sun Z, Shi Y, Shen Y, Cao L, Zhang W, Guan X. Analysis of different HER-2 mutations in breast cancer progression and drug resistance. J Cell Mol Med 2015; 19:2691-701. [PMID: 26305917 PMCID: PMC4687700 DOI: 10.1111/jcmm.12662] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2015] [Accepted: 07/03/2015] [Indexed: 12/17/2022] Open
Abstract
Studies over the last two decades have identified that amplified human epidermal growth factor receptor (HER‐2; c‐erbB‐2, neu) and its overexpression have been frequently implicated in the carcinogenesis and prognosis in a variety of solid tumours, especially breast cancer. Lots of painstaking efforts were invested on the HER‐2 targeted agents, and significantly improved outcome and prolonged the survival of patients. However, some patients classified as ‘HER‐2‐positive’ would be still resistant to the anti‐HER‐2 therapy. Various mechanisms of drug resistance have been illustrated and the alteration of HER‐2 was considered as a crucial mechanism. However, systematic researches in regard to the HER‐2 mutations and variants are still inadequate. Notably, the alterations of HER‐2 play an important role in drug resistance, but also have a potential association with the cancer risk. In this review, we summarize the possible mutations and focus on HER‐2 variants’ role in breast cancer tumourigenesis. Additionally, the alteration of HER‐2, as a potential mechanism of resistance to trastuzumab, is discussed here. We hope that HER‐2 related activating mutations could potentially offer more therapeutic opportunities to a broader range of patients than previously classified as HER‐2 overexpressed.
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Affiliation(s)
- Zijia Sun
- Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Yaqin Shi
- Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Yan Shen
- Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Lulu Cao
- Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Wenwen Zhang
- Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
| | - Xiaoxiang Guan
- Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing, China.,Department of Medical Oncology, Jinling Hospital, School of Medicine, Southern Medical University, Guangzhou, China
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Mizuguchi Y, Specht S, Isse K, Sasatomi E, Lunz JG, Takizawa T, Demetris AJ. Breast tumor kinase/protein tyrosine kinase 6 (Brk/PTK6) activity in normal and neoplastic biliary epithelia. J Hepatol 2015; 63:399-407. [PMID: 25770659 DOI: 10.1016/j.jhep.2015.02.047] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/14/2014] [Revised: 01/23/2015] [Accepted: 02/25/2015] [Indexed: 12/04/2022]
Abstract
BACKGROUND & AIMS Breast tumor kinase (BRK) augments proliferation and promotes cell survival in breast cancers via interactions with SH2 and SH3 ligand-containing proteins, such as receptor tyrosine kinases (RTK; e.g. EGFR, ErbB2/neu). Since RTK contribute to cholangiocarcinoma (CC) evolution we probed BRK protein expression and function in normal and CC livers. METHODS Immunohistochemical staining of normal livers and CC (n=93) in a tissue microarray and three CC and an immortalized human cholangiocyte cell lines (real-time PCR, Western blotting, siRNA) were used to study the functional relationships between BRK, EGFR, ErbB2, SAM68, and SPRR2a. RESULTS BRK protein was expressed in normal human intrahepatic bile ducts; all CC cell lines and a majority of CC showed strong BRK protein expression. Multiplex immunostaining/tissue cytometry and immunoprecipitation studies showed: 1) BRK co-localized with EGFR and ErbB2/neu; 2) BRK(high)/EGFR(high)-co-expressing CC cells had significantly higher Ki67 labeling and; 3) stronger BRK protein expression was seen in perihilar and distal CC than intrahepatic CC and directly correlated with CC differentiation. In cell lines, BRK expression augmented proliferation in response to exogenous EGF, whereas BRK siRNA significantly reduced growth. The SH3 ligand-containing, SPRR2A activated pTyr342 BRK, which in turn, phosphorylated SAM68, causing nuclear localization and increased cell proliferation similar to observations in breast cancers. CONCLUSION BRK expression in a majority of CC can interact with RTK, augmenting growth and interfering with proliferation inhibitors (SAM68). Therapeutically targeting BRK function (in addition to RTK) should be of benefit for CC treatment.
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Affiliation(s)
- Yoshiaki Mizuguchi
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, PA 15260, USA; The Department of Pathology, Division of Liver and Transplantation Pathology, University of Pittsburgh Medical Center, PA 15260, USA
| | - Susan Specht
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, PA 15260, USA; The Department of Pathology, Division of Liver and Transplantation Pathology, University of Pittsburgh Medical Center, PA 15260, USA
| | - Kumiko Isse
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, PA 15260, USA; The Department of Pathology, Division of Liver and Transplantation Pathology, University of Pittsburgh Medical Center, PA 15260, USA
| | - Eizaburo Sasatomi
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, PA 15260, USA; The Department of Pathology, Division of Liver and Transplantation Pathology, University of Pittsburgh Medical Center, PA 15260, USA
| | - John G Lunz
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, PA 15260, USA; The Department of Pathology, Division of Liver and Transplantation Pathology, University of Pittsburgh Medical Center, PA 15260, USA
| | - Toshihiro Takizawa
- Department of Molecular Anatomy and Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-Ku, Tokyo 113-8602, Japan
| | - Anthony J Demetris
- Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, PA 15260, USA; The Department of Pathology, Division of Liver and Transplantation Pathology, University of Pittsburgh Medical Center, PA 15260, USA.
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Poh AR, O'Donoghue RJ, Ernst M. Hematopoietic cell kinase (HCK) as a therapeutic target in immune and cancer cells. Oncotarget 2015; 6:15752-71. [PMID: 26087188 PMCID: PMC4599235 DOI: 10.18632/oncotarget.4199] [Citation(s) in RCA: 95] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Accepted: 05/29/2015] [Indexed: 12/21/2022] Open
Abstract
The hematopoietic cell kinase (HCK) is a member of the SRC family of cytoplasmic tyrosine kinases (SFKs), and is expressed in cells of the myeloid and B-lymphocyte cell lineages. Excessive HCK activation is associated with several types of leukemia and enhances cell proliferation and survival by physical association with oncogenic fusion proteins, and with functional interactions with receptor tyrosine kinases. Elevated HCK activity is also observed in many solid malignancies, including breast and colon cancer, and correlates with decreased patient survival rates. HCK enhances the secretion of growth factors and pro-inflammatory cytokines from myeloid cells, and promotes macrophage polarization towards a wound healing and tumor-promoting alternatively activated phenotype. Within tumor associated macrophages, HCK stimulates the formation of podosomes that facilitate extracellular matrix degradation, which enhance immune and epithelial cell invasion. By virtue of functional cooperation between HCK and bona fide oncogenic tyrosine kinases, excessive HCK activation can also reduce drug efficacy and contribute to chemo-resistance, while genetic ablation of HCK results in minimal physiological consequences in healthy mice. Given its known crystal structure, HCK therefore provides an attractive therapeutic target to both, directly inhibit the growth of cancer cells, and indirectly curb the source of tumor-promoting changes in the tumor microenvironment.
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Affiliation(s)
- Ashleigh R. Poh
- The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Victoria, Australia
| | - Robert J.J. O'Donoghue
- The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Victoria, Australia
- Olivia Newton-John Cancer Research Institute, La Trobe University School of Cancer Medicine, Victoria, Australia
| | - Matthias Ernst
- The Walter and Eliza Hall Institute of Medical Research, Department of Medical Biology, University of Melbourne, Victoria, Australia
- Olivia Newton-John Cancer Research Institute, La Trobe University School of Cancer Medicine, Victoria, Australia
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Jha P, Lu D, Yuan Y, Xu S. Signature of positive selection of PTK6 gene in East Asian populations: a cross talk for Helicobacter pylori invasion and gastric cancer endemicity. Mol Genet Genomics 2015; 290:1741-52. [PMID: 25838168 DOI: 10.1007/s00438-015-1032-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2014] [Accepted: 03/20/2015] [Indexed: 01/22/2023]
Abstract
Analysis of natural selection events is an attractive strategy for identification of functional variants shaped by gene-environmental interactions and human adaptation. Here, we identified PTK6, a Src-related tyrosine kinase gene, underlying positive selection in East Asian populations. Interestingly, PTK6 variant showed significant correlation with gastric cancer incidences which was the highest in East Asian populations. The high prevalence of gastric cancer in East Asians was also believed to be strongly affected by Helicobacter pylori infection and dietary habit. Therefore, we speculated a competitive interaction of cancer-associated molecules for activation/reduction, where PTK6 likely plays a role through CagA-driven signaling pathway after H. pylori infection. This hypothesis was also supported by our gene expression analysis and the dating of the selective event which was estimated to be ~16,500 years ago, much later than H. pylori invasion in human 50,000 years ago. Establishment of cross talk between PTK6 and CagA by functional studies may further elucidate the underlying biology of H. pylori-mediated gastric cancer.
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Affiliation(s)
- Pankaj Jha
- Chinese Academy of Sciences (CAS) Key Laboratory of Computational Biology, Max Planck Independent Research Group on Population Genomics, CAS-MPG Partner Institute for Computational Biology (PICB), Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Dongsheng Lu
- Chinese Academy of Sciences (CAS) Key Laboratory of Computational Biology, Max Planck Independent Research Group on Population Genomics, CAS-MPG Partner Institute for Computational Biology (PICB), Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Yuan Yuan
- Chinese Academy of Sciences (CAS) Key Laboratory of Computational Biology, Max Planck Independent Research Group on Population Genomics, CAS-MPG Partner Institute for Computational Biology (PICB), Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Shuhua Xu
- Chinese Academy of Sciences (CAS) Key Laboratory of Computational Biology, Max Planck Independent Research Group on Population Genomics, CAS-MPG Partner Institute for Computational Biology (PICB), Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China.
- School of Life Science and Technology, ShanghaiTec University, Shanghai, 200031, China.
- Collaborative Innovation Center of Genetics and Development, Shanghai, 200438, China.
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Rasmussen NR, Debebe Z, Wright TM, Brooks SA, Sendor AB, Brannon A.R, Hakimi A.A, Hsieh JJ, Choueiri TK, Tamboli P, Maranchie JK, Hinds P, Wallen EM, Simpson C, Norris JL, Janzen WP, Rathmell WK. Expression of Ror2 mediates invasive phenotypes in renal cell carcinoma. PLoS One 2014; 9:e116101. [PMID: 25542006 PMCID: PMC4277431 DOI: 10.1371/journal.pone.0116101] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Accepted: 12/04/2014] [Indexed: 11/18/2022] Open
Abstract
Ror2 is a Wnt ligand receptor that is overexpressed in a variety of tumors including clear cell renal cell carcinoma (ccRCC). Here we demonstrate that expression of wild type Ror2 results in increased tumorigenic properties in in vitro cell culture and in vivo xenograft models. In addition, Ror2 expression produced positive changes in both cell migration and invasion, which were dependent on matrix metalloprotease 2 (MMP2) activity. Mutations in key regions of the kinase domain of Ror2 resulted in the abrogation of increased tumor growth, cell migration, and cell invasion observed with expression of wild-type Ror2. Finally, we examined Ror2 expression as a prognostic biomarker for ccRCC utilizing the TCGA ccRCC dataset. High expression of Ror2 showed a significant correlation with higher clinical stage, nuclear grade, and tumor stage. Furthermore, high expression of Ror2 in ccRCC patients correlated with significant lower overall survival, cancer specific survival, and recurrence free survival. Together, these findings suggest that Ror2 plays a central role in influencing the ccRCC phenotype, and can be considered as a negative prognostic biomarker and potential therapeutic target in this cancer.
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Affiliation(s)
- Neal R. Rasmussen
- Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, United States of America
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, United States of America
| | - Zufan Debebe
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, United States of America
| | - Tricia M. Wright
- Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, United States of America
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, United States of America
| | - Samira A. Brooks
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, United States of America
- Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, United States of America
| | - Adam B. Sendor
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, United States of America
| | - A . Rose Brannon
- Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, United States of America
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, United States of America
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, 10065, United States of America
| | - A . Ari Hakimi
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, 10065, United States of America
- Department of Surgery, Urology Service, Memorial Sloan Kettering Cancer Center, New York, New York, 10065, United States of America
| | - James J. Hsieh
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, 10065, United States of America
- Department of Surgery, Urology Service, Memorial Sloan Kettering Cancer Center, New York, New York, 10065, United States of America
| | - Toni K. Choueiri
- Department of Medical Oncology and Kidney Cancer Center, Dana Farber Cancer Institute, Boston, Massachusetts, 02215, United States of America
| | - Pheroze Tamboli
- Department of Pathology, MD Anderson Cancer Center, Houston, Texas, 77030, United States of America
| | - Jodi K. Maranchie
- Department of Urologic Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, 15219, United States of America
| | - Peter Hinds
- Department of Urologic Oncology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, 15219, United States of America
| | - Eric M. Wallen
- Department of Urology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, United States of America
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, United States of America
| | - Catherine Simpson
- Center for Integrative Chemical Biology and Drug Discovery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, United States of America
| | - Jacqueline L. Norris
- Center for Integrative Chemical Biology and Drug Discovery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, United States of America
| | - William P. Janzen
- Center for Integrative Chemical Biology and Drug Discovery, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, United States of America
| | - W. Kimryn Rathmell
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, United States of America
- Departments of Medicine and Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599, United States of America
- * E-mail:
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Graham DK, DeRyckere D, Davies KD, Earp HS. The TAM family: phosphatidylserine sensing receptor tyrosine kinases gone awry in cancer. Nat Rev Cancer 2014; 14:769-85. [PMID: 25568918 DOI: 10.1038/nrc3847] [Citation(s) in RCA: 555] [Impact Index Per Article: 50.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
The TYRO3, AXL (also known as UFO) and MERTK (TAM) family of receptor tyrosine kinases (RTKs) are aberrantly expressed in multiple haematological and epithelial malignancies. Rather than functioning as oncogenic drivers, their induction in tumour cells predominately promotes survival, chemoresistance and motility. The unique mode of maximal activation of this RTK family requires an extracellular lipid–protein complex. For example, the protein ligand, growth arrest-specific protein 6 (GAS6), binds to phosphatidylserine (PtdSer) that is externalized on apoptotic cell membranes, which activates MERTK on macrophages. This triggers engulfment of apoptotic material and subsequent anti-inflammatory macrophage polarization. In tumours, autocrine and paracrine ligands and apoptotic cells are abundant, which provide a survival signal to the tumour cell and favour an anti-inflammatory, immunosuppressive microenvironment. Thus, TAM kinase inhibition could stimulate antitumour immunity, reduce tumour cell survival, enhance chemosensitivity and diminish metastatic potential.
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26
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Liu LN, Huang PY, Lin ZR, Hu LJ, Liang JZ, Li MZ, Tang LQ, Zeng MS, Zhong Q, Zeng BH. Protein tyrosine kinase 6 is associated with nasopharyngeal carcinoma poor prognosis and metastasis. J Transl Med 2013; 11:140. [PMID: 23758975 PMCID: PMC3686693 DOI: 10.1186/1479-5876-11-140] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2013] [Accepted: 06/03/2013] [Indexed: 12/16/2022] Open
Abstract
Background The aim of this study was to analyze the expression of protein tyrosine kinase 6 (PTK6) in nasopharyngeal carcinoma (NPC) samples, and to identify whether PTK6 can serve as a biomarker for the diagnosis and prognosis of NPC. Methods We used quantitative RT-PCR and Western blotting analysis to detect mRNA and protein expression of PTK6 in NPC cell lines and immortalized nasopharyngeal epithelial cell lines. 31 NPC and 16 non-tumorous nasopharyngeal mucosa biopsies were collected to detect the difference in the expression of mRNA level of PTK6 by quantitative RT-PCR. We also collected 178 NPC and 10 normal nasopharyngeal epithelial cases with clinical follow-up data to investigate the expression of PTK6 by immunohistochemistry staining (IHC). PTK6 overexpression on cell growth and colony formation ability were measured by the method of cell proliferation assay and colony formation assay. Results The expression of PTK6 was higher in most of NPC cell lines at both mRNA and protein levels than in immortalized nasopharyngeal epithelial cell lines (NPECs) induced by Bmi-1 (Bmi-1/NPEC1, and Bmi-1/NPEC2). The mRNA level of PTK6 was high in NPC biopsies compared to non-tumorous nasopharyngeal mucosa biopsies. IHC results showed the expression of PTK6 was significantly correlated to tumor size (P<0.001), clinical stage (P<0.001), and metastasis (P=0.016). The patients with high-expression of PTK6 had a significantly poor prognosis compared to those of low-expression (47.8% versus 80.0%, P<0.001), especially in the patients at the advanced stages (42.2% versus 79.1%, P<0.001). Multivariate analysis indicated that the level of PTK6 expression was an independent prognostic factor for the overall survival of patients with NPC (P <0.001). Overexpression of PTK6 in HNE1 cells enhanced the ability of cell proliferation and colony formation. Conclusions Our results suggest that high-expression of PTK6 is an independent factor for NPC patients and it might serve as a potential prognostic biomarker for patients with NPC.
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Affiliation(s)
- Li-na Liu
- Department of Oncology, Second Affiliated Hospital of Guangzhou medical college, 250 Changgang Road East, Guangzhou 510260, China
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Ford CE, Qian Ma SS, Quadir A, Ward RL. The dual role of the novel Wnt receptor tyrosine kinase, ROR2, in human carcinogenesis. Int J Cancer 2013; 133:779-87. [PMID: 23233346 DOI: 10.1002/ijc.27984] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2012] [Revised: 11/21/2012] [Accepted: 11/29/2012] [Indexed: 01/31/2023]
Abstract
The Wnt signaling pathway is involved in the development and progression of many human cancers, yet attempts to target the pathway therapeutically have been disappointing to date. The recent discovery that the ROR2 receptor tyrosine kinase (RTK) is a novel Wnt receptor provides the potential to target the non-canonical Wnt pathway for cancer treatments. As a member of the RTK superfamily of surface receptors ROR2 appears to possess dual roles as a tumor suppressor or activator depending on tumor type. This review will explore the dual role of ROR2 in tumorigenesis and provide an up to date analysis of current literature in this rapidly expanding field.
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Affiliation(s)
- Caroline E Ford
- Wnt Signaling & Metastasis Group, Lowy Cancer Research Centre and Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Australia.
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Daneshmanesh AH, Porwit A, Hojjat-Farsangi M, Jeddi-Tehrani M, Tamm KP, Grandér D, Lehmann S, Norin S, Shokri F, Rabbani H, Mellstedt H, Österborg A. Orphan receptor tyrosine kinases ROR1 and ROR2 in hematological malignancies. Leuk Lymphoma 2012; 54:843-50. [PMID: 22988987 DOI: 10.3109/10428194.2012.731599] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
The receptor tyrosine kinase ROR1 has been shown to be overexpressed in chronic lymphocytic leukemia (CLL). The aim of this study was to further characterize the expression of ROR1 and the other member of the ROR family, ROR2, in other lymphoid and myeloid malignancies. Normal white blood cells and reactive lymph nodes were negative for ROR1 and ROR2. A significantly high and uniform surface expression of ROR1 was found in CLL/hairy cell leukemia (HCL) compared to mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), myelomas, acute lymphoblastic leukemia (ALL) and myeloid leukemias (p = 0.02 to < 0.001). The lowest proportion of ROR1+ cells was seen in FL, whereas CLL, HCL and CML had significantly higher numbers of ROR1+ cells. Longitudinal follow-up of individual patients with CLL revealed that ROR1+ cells remained stable over time in non-progressive patients, but increased when the disease progressed (p < 0.05). Thus, a variable staining pattern of ROR1 ranging from very high (CLL, HCL) and high (CML) to intermediate (myeloma and DLBCL) or low (FL) was noted. ROR2 was not detected in hematological malignancies.
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Affiliation(s)
- Amir Hossein Daneshmanesh
- Immune and Gene Therapy Laboratory, Cancer Center Karolinska, Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, Sweden
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Kiyose SI, Nagura K, Tao H, Igarashi H, Yamada H, Goto M, Maeda M, Kurabe N, Suzuki M, Tsuboi M, Kahyo T, Shinmura K, Hattori N, Sugimura H. Detection of kinase amplifications in gastric cancer archives using fluorescence in situ hybridization. Pathol Int 2012; 62:477-484. [PMID: 22691185 DOI: 10.1111/j.1440-1827.2012.02832.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
To test the feasibility of using bacterial artificial chromosomes (BAC) containing kinases for pathological diagnosis using fluorescence in situ hybridization (FISH), 10 BAC probes containing a gene amplified in 5% or more of a pilot cohort were selected from a previous survey using arbitrarily selected BAC clones harboring 100 kinases. In this report, we describe the prevalence and association with the clinicopathological profile of these selected 10 BAC probes in 365 gastric cancer tissues. FISH analyses using these 10 BAC probes containing loci encoding EGFR, ERBB2(HER2), EPHB3, PIK3CA, MET, PTK7, ACK1, STK15, SRC, and HCK showed detectable amplifications in paraffin-embedded tissue in 2.83% to 13.6% of the gastric cancer tissues. Considerable numbers of the cases showed the co-amplification of two or more of the probes that were tested. BAC probes located within a genome neighborhood, such as PIK3CA, EPHB3, and ACK1 at 3q26-29 or HCK, SRC, and STK15 at 20q11-13.1, were often co-amplified in the same cases, but non-random co-amplifications of genes at distant genomic loci were also observed. These findings provide basic information regarding the creation of a strategy for personalizing gastric cancer therapy, especially when using multiple kinase inhibitors.
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Affiliation(s)
- Shin-ichiro Kiyose
- Department of Tumor Pathology, Hamamatsu University School of Medicine, Higashi-ku, Hamamatsu, Japan
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Differential sensitivity of ERBB2 kinase domain mutations towards lapatinib. PLoS One 2011; 6:e26760. [PMID: 22046346 PMCID: PMC3203921 DOI: 10.1371/journal.pone.0026760] [Citation(s) in RCA: 106] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2011] [Accepted: 10/03/2011] [Indexed: 11/22/2022] Open
Abstract
Background Overexpression of the ERBB2 kinase is observed in about one-third of breast cancer patients and the dual ERBB1/ERBB2 kinase inhibitor lapatinib was recently approved for the treatment of advanced ERBB2-positive breast cancer. Mutations in the ERBB2 receptor have recently been reported in breast cancer at diagnosis and also in gastric, colorectal and lung cancer. These mutations may have an impact on the clinical responses achieved with lapatinib in breast cancer and may also have a potential impact on the use of lapatinib in other solid cancers. However, the sensitivity of lapatinib towards clinically observed ERBB2 mutations is not known. Methodology/Principal Findings We cloned a panel of 8 clinically observed ERBB2 mutations, established stable cell lines and characterized their sensitivity towards lapatinib and alternative ERBB2 inhibitors. Both lapatinib-sensitive and lapatinib-resistant ERBB2 mutations were observed. Interestingly, we were able to generate lapatinib resistance mutations in wt-ERBB2 cells incubated with lapatinib for prolonged periods of time. This indicates that these resistance mutations may also cause secondary resistance in lapatinib-treated patients. Lapatinib-resistant ERBB2 mutations were found to be highly resistant towards AEE788 treatment but remained sensitive towards the dual irreversible inhibitors CL-387785 and WZ-4002. Conclusions/Significance Patients harbouring certain ERBB2 kinase domain mutations at diagnosis may not benefit from lapatinib treatment. Moreover, secondary lapatinib resistance may develop due to kinase domain mutations. Irreversible ERBB2 inhibitors may offer alternative treatment options for breast cancer and other solid tumor patients harbouring lapatinib resistance mutations. In addition, these inhibitors may be of interest in the scenario of secondary lapatinib resistance.
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Liu L, Shi H, Liu Y, Anderson A, Peterson J, Greger J, Martin AM, Gilmer TM. Synergistic effects of foretinib with HER-targeted agents in MET and HER1- or HER2-coactivated tumor cells. Mol Cancer Ther 2011; 10:518-30. [PMID: 21252284 DOI: 10.1158/1535-7163.mct-10-0698] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The HER and MET receptor tyrosine kinases (RTK) are coactivated in a subset of human tumors. This study characterizes MET and HER expression and signaling in a panel of human tumor cell lines and the differential susceptibility of these cell lines to single agents or combinations of foretinib, a multikinase MET inhibitor, with HER-targeted agents, erlotinib or lapatinib. Most MET-amplified tumor lines without HER1 or HER2 amplification are sensitive to foretinib, whereas MET-amplified lines with HER1 or HER2 amplification are more sensitive to the combination of foretinib with lapatinib or erlotinib. Interestingly, MET-overexpressing tumor cell lines with HER1 or HER2 amplification also exhibited reduced sensitivity to lapatinib or erlotinib in the presence of hepatocyte growth factor (HGF), indicating MET activation can decrease the effectiveness of HER1/2 inhibitors in some cell lines. Consistent with this observation, the effect of HGF on lapatinib or erlotinib sensitivity in these cells was reversed by foretinib, other MET inhibitors, or siRNA to MET. Western blot analyses showed that combining foretinib with erlotinib or lapatinib effectively decreased the phosphorylation of MET, HER1, HER2, HER3, AKT, and ERK in these cells. Furthermore, HER2-positive advanced or metastatic breast cancer patients treated with lapatinib who had higher tumor MET expression showed shorter progression-free survival (19.29 weeks in MET-high patients vs. 28.14 weeks in MET-low patients, P < 0.0225). These data suggest that combination therapy with foretinib and HER-targeted agents should be tested as a treatment option for HER1- or HER2-positive patients with MET-amplified or -overexpressing tumors.
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Affiliation(s)
- Li Liu
- GlaxoSmithKline, 17.1356I, 5 Moore Drive, Research Triangle Park, NC 27709-3398, USA
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Brauer PM, Tyner AL. Building a better understanding of the intracellular tyrosine kinase PTK6 - BRK by BRK. BIOCHIMICA ET BIOPHYSICA ACTA 2010; 1806:66-73. [PMID: 20193745 PMCID: PMC2885473 DOI: 10.1016/j.bbcan.2010.02.003] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/16/2009] [Revised: 02/17/2010] [Accepted: 02/19/2010] [Indexed: 01/21/2023]
Abstract
Protein tyrosine kinase 6 (PTK6), also referred to as breast tumor kinase BRK, is a member of a distinct family of kinases that is evolutionarily related to the SRC family of tyrosine kinases. While not expressed in the normal mammary gland, PTK6 expression is detected in a large proportion of human mammary gland tumors. In breast tumor cells, PTK6 promotes growth factor signaling and cell migration. PTK6 expression is also increased in a number of other epithelial tumors, including ovarian and colon cancer. In contrast, PTK6 is expressed in diverse normal epithelia, including the linings of the gastrointestinal tract, skin and prostate, where its expression correlates with cell cycle exit and differentiation. Disruption of the mouse Ptk6 gene leads to increased growth and impaired differentiation in the small intestine that is accompanied by increased AKT and Wnt signaling. Following total body irradiation, PTK6 expression is induced in proliferating progenitor cells of the intestine, where it plays an essential role in DNA-damage induced apoptosis. A distinguishing feature of PTK6 is its flexibility in intracellular localization, due to a lack of amino-terminal myristoylation/palmitoylation. Recently a number of substrates of PTK6 have been identified, including nuclear RNA-binding proteins and transcription factors. We discuss PTK6 signaling, its apparent conflicting roles in cancer and normal epithelia, and its potential as a therapeutic target in epithelial cancers.
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Affiliation(s)
- Patrick M. Brauer
- Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607, USA
| | - Angela L. Tyner
- Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL 60607, USA
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Sugimura H, Mori H, Nagura K, Kiyose SI, Tao H, Isozaki M, Igarashi H, Shinmura K, Hasegawa A, Kitayama Y, Tanioka F. Fluorescence in situ hybridization analysis with a tissue microarray: 'FISH and chips' analysis of pathology archives. Pathol Int 2010; 60:543-550. [PMID: 20618731 DOI: 10.1111/j.1440-1827.2010.02561.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Practicing pathologists expect major somatic genetic changes in cancers, because the morphological deviations in the cancers they diagnose are so great that the somatic genetic changes to direct these phenotypes of tumors are supposed to be correspondingly tremendous. Several lines of evidence, especially lines generated by high-throughput genomic sequencing and genome-wide analyses of cancer DNAs are verifying their preoccupations. This article reviews a comprehensive morphological approach to pathology archives that consists of fluorescence in situ hybridization with bacterial artificial chromosome (BAC) probes and screening with tissue microarrays to detect structural changes in chromosomes (copy number alterations and rearrangements) in specimens of human solid tumors. The potential of this approach in the attempt to provide individually tailored medical practice, especially in terms of cancer therapy, is discussed.
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Affiliation(s)
- Haruhiko Sugimura
- Department of Pathology, Hamamamatsu University School of Medicine, 1-20-1, Handayama, Higashi-ward, Hamamatsu 431-3192, Japan.
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Wright TM, Rathmell WK. Identification of Ror2 as a hypoxia-inducible factor target in von Hippel-Lindau-associated renal cell carcinoma. J Biol Chem 2010; 285:12916-24. [PMID: 20185829 PMCID: PMC2857057 DOI: 10.1074/jbc.m109.073924] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2009] [Revised: 02/24/2010] [Indexed: 11/06/2022] Open
Abstract
Ror2 is an orphan receptor tyrosine kinase with expression normally restricted to early stages of development. However, emerging evidence has placed aberrantly expressed Ror2, leading to an invasive phenotype, in several cancers including renal cell carcinoma (RCC). Although Ror2 is currently identified as up-regulated in an assortment of cancers, neither the regulatory role or mechanism of action have been delineated. We sought to place Ror2 in the most commonly mutated pathway of RCC, the loss of the tumor suppressor von Hippel-Lindau (VHL), which causes hypoxia-inducible factor (HIF)-1alpha and -2alpha stabilization and the transcriptional activation of a broad repertoire of response genes. We found that Ror2 was indeed associated with the pVHL loss in RCC as well as with VHL somatic mutations tightly coordinated with the induction of RCC. Additionally, knockdown and rescue analysis of HIF expression suggests that Ror2 is dependent on pathologic stabilization of either HIF-1alpha or HIF-2alpha. Subsequent evaluation of the ROR2 promoter suggests that HIF-2alpha and its dimerization partner, aryl hydrocarbon nuclear transferase localize to the ROR2 promoter via a cryptic transcriptional element. This data substantiates a unique regulation pattern for Ror2 in the VHL-HIF axis that has the potential to be applied to other cancer etiologies.
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Affiliation(s)
- Tricia M. Wright
- From the Department of Genetics, Curriculum in Genetics and Molecular Biology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599
| | - W. Kimryn Rathmell
- From the Department of Genetics, Curriculum in Genetics and Molecular Biology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina 27599
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Abstract
As the upward spiral of novel cancer gene discoveries and novel molecular compounds continues to accelerate, a repetitive theme in molecular drug development remains the lack of activity of initially promising agents when given to patients in clinical trials. It is however invigorating that a few targeted agents directed against a select group of a few 'cancer gene superfamilies' have escaped this all to common fate, and have evolved into novel, clinically meaningful molecular therapy strategies. Targeting dysregulated signaling of the epidermal growth factor family of transmembrane receptors (Erbb family) has encompassed over the last decade an ever increasing role in personalized treatment approaches in an increasing number of human malignancies. Erbbs are receptor tyrosine kinases that are important regulators of several signaling pathways. Two of its family members (Erbb1/EGFR and Erbb2/HER2) have previously been shown to be somatically mutated in large fraction of human cancers. To determine if this family is somatically mutated in melanoma, its sequences were recently analyzed and one of its members, Erbb4, was found to be somatically mutated in 19% of melanoma cases. Functional analysis of seven of its mutations was shown to increase its catalytic and transformation abilities as well as providing essential survival signals. Similar to other Erbb family members, mutant Erbb4 seems to confer 'oncogene addiction' on melanoma cells, making it an attractive therapeutic target. Gaining further understanding into the oncogenic mechanism of Erbb4 may not only help in the development of targeted therapy in melanoma patients but might accelerate the acceptance of a novel taxonomy of cancer which is based on the genomic perturbations in cancer genes and cancer gene families and their response to targeted agents.
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Affiliation(s)
- Udo Rudloff
- National Cancer Institute, Surgery Branch, Bethesda, MD, USA
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