Global tyrosine kinome profiling of human thyroid tumors identifies Src as a promising target for invasive cancers

Cho, Nancy L.; Lin, Chi Iou; Du, Jinyan; Whang, Edward E.; Ito, Hiromichi; Moore, Francis D.; Ruan, Daniel T.

doi:10.1016/j.bbrc.2012.04.034

Cited by 16 publications

(9 citation statements)

References 22 publications

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“…Finally, investigators are using kinome profiling, studying kinase complement of the human genome, combined with other transcriptional phosphoproteomics studies, to look for new treatment targets and strategies enhancing the currently available MKIs. One recent report identified SRC kinases as targets for invasive thyroid tumors using kinase phosphorylation assay [ 93 ]. Another report, using global phosphoproteomics analysis, identified CK2 (Caseine Kinsase 2) as a survival mechanism after BRAF-MEK signaling blockade [ 94 ].…”

Section: Future Directions For Scientific and Clinical Communitymentioning

confidence: 99%

Novel targeted therapies and immunotherapy for advanced thyroid cancers

et al. 2018

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Thyroid cancer is a frequently encountered endocrine malignancy. Despite the favorable prognosis of this disease, 15–20% of differentiated thyroid cancer (DTC) cases and most anaplastic types, remain resistant to standard treatment options, including radioactive iodine (RAI). In addition, around 30% of medullary thyroid cancer (MTC) cases show resistance after surgery. The evolving understanding of disease-specific molecular therapeutic targets has led to the approval of two targeted therapies (Sorafenib and Lenvatinib) for RAI refractory DTC and another two drugs (Vandetanib and Cabozantinib) for MTC. These advanced therapies exert their effects by blocking the MAPK pathway, which has been widely correlated to different types of thyroid cancers. While these drugs remain reserved for thyroid cancer patients who failed all treatment options, their ability to improve patients’ overall survival remain hindered by their low efficacy and other molecular factors. Among these factors is the tumor’s ability to activate parallel proliferative signaling pathways other than the cascades blocked by these drugs, along with overexpression of some tyrosine kinase receptors (TKR). These facts urge the search for novel different treatment strategies for advanced thyroid cases beyond these drugs. Furthermore, the growing knowledge of the dynamic immune system interaction with tumor microenvironment has revolutionized the cancer immune therapy field. In this review, we aim to discuss the molecular escape mechanisms of thyroid tumors from these drugs. We also highlight novel therapeutic options targeting other pathways than MAPK, including PI3K pathway, ALK translocations and HER2/3 receptors and their clinical impact. We also aim to discuss the usage of targeted therapy in restoring thyroid tumor sensitivity to RAI, and finally turn to extensively discuss the role of immunotherapy as a potential alternative treatment option for advanced thyroid diseases.Electronic supplementary materialThe online version of this article (10.1186/s12943-018-0786-0) contains supplementary material, which is available to authorized users.

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Section: Future Directions For Scientific and Clinical Communitymentioning

confidence: 99%

Novel targeted therapies and immunotherapy for advanced thyroid cancers

et al. 2018

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“…TNK1 (thirty-eight-negative kinase 1), another important member of ACK family NRTKs of size about 72 KDa, was first reported in blood stem cells of human umbilical cord and murine embryonic cells [ 16 , 94 ]. Available literature reveals that TNK1 has both tumor suppressing and oncogenic potential as it can mitigate the growth of tumor cells by dowenregulating Ras-Raf1-MAPK pathway [ 95 ], induce apoptosis through NF-κB inhibition [ 96 ], activate cellular transformation and growth of neoplastic cells [ 97 , 98 ]. TNK1 sorted out as an important kinase with oncogenic potential implicated in hematological carcinogenesis such as in AML and Hodgkin’s Lymphoma which suggests that targeted intervention of TNK1 may open new platform for therapy.…”

Section: Non Receptor Tyrosine Kinase Familiesmentioning

confidence: 99%

Role of Non Receptor Tyrosine Kinases in Hematological Malignances and its Targeting by Natural Products

et al. 2018

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Tyrosine kinases belong to a family of enzymes that mediate the movement of the phosphate group to tyrosine residues of target protein, thus transmitting signals from the cell surface to cytoplasmic proteins and the nucleus to regulate physiological processes. Non-receptor tyrosine kinases (NRTK) are a sub-group of tyrosine kinases, which can relay intracellular signals originating from extracellular receptor. NRTKs can regulate a huge array of cellular functions such as cell survival, division/propagation and adhesion, gene expression, immune response, etc. NRTKs exhibit considerable variability in their structural make up, having a shared kinase domain and commonly possessing many other domains such as SH2, SH3 which are protein-protein interacting domains. Recent studies show that NRTKs are mutated in several hematological malignancies, including lymphomas, leukemias and myelomas, leading to aberrant activation. It can be due to point mutations which are intragenic changes or by fusion of genes leading to chromosome translocation. Mutations that lead to constitutive kinase activity result in the formation of oncogenes, such as Abl, Fes, Src, etc. Therefore, specific kinase inhibitors have been sought after to target mutated kinases. A number of compounds have since been discovered, which have shown to inhibit the activity of NRTKs, which are remarkably well tolerated. This review covers the role of various NRTKs in the development of hematological cancers, including their deregulation, genetic alterations, aberrant activation and associated mutations. In addition, it also looks at the recent advances in the development of novel natural compounds that can target NRTKs and perhaps in combination with other forms of therapy can show great promise for the treatment of hematological malignancies.

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“…Although PTK6 is not expressed in the normal human mammary gland, it is aberrantly expressed in a high percentage of breast tumours . Elevated expression of PTK6 has also been detected in other types of cancer including colon , prostate , head and neck cancer , serous carcinoma of ovary , lung and thyroid cancer . Recently, however, expression of PTK6 transcripts was found to be downregulated in oesophageal squamous carcinomas as a consequence of epigenetic modification, and PTK6 appears to have tumour suppressor activities in this type of cancer .…”

Section: Different Roles For Ptk6 In Normal Tissues and Cancermentioning

confidence: 99%

Context‐specific protein tyrosine kinase 6 (PTK6) signalling in prostate cancer

Zheng

Tyner

2013

Eur J Clin Investigation

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Background PTK6 is an intracellular tyrosine kinase that is distantly related to SRC family kinases. PTK6 is nuclear in normal prostate epithelia, but nuclear localization is lost in prostate tumors. Increased expression of PTK6 is detected in human prostate cancer, especially at metastatic stages, and in other types of cancers, including breast, colon, head and neck cancers, and serous carcinoma of ovary. Materials and Methods Potential novel substrates of PTK6 identified by mass spectrometry were validated in vitro. The significance of PTK6 induced phosphorylation of these substrates was addressed using human prostate cell lines by knockdown of endogenous PTK6, or overexpression of targeted PTK6 to different intracellular compartments. Results We identified AKT, p130CAS and FAK as novel PTK6 substrates and demonstrated their roles in promoting cell proliferation, migration, and resistance to anoikis. In prostate cancer cells, active PTK6 is primarily associated with membrane compartments, although the majority of total PTK6 is localized within the cytoplasm. Ectopic expression of membrane-targeted PTK6 transforms immortalized fibroblasts. Knockdown of endogenous cytoplasmic PTK6 in PC3 prostate cancer cells impairs proliferation, migration, and anoikis resistance. However, reintroduction of PTK6 into the nucleus significantly decreases cell proliferation, suggesting context specific functions for nuclear PTK6. Conclusions In human prostate cancer, elevated PTK6 expression, translocation of PTK6 from the nucleus to the cytoplasm, and its activation at the plasma membrane, contribute to increased phosphorylation and activation of its substrates such as AKT, p130CAS and FAK, thereby promoting prostate cancer progression.

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Global tyrosine kinome profiling of human thyroid tumors identifies Src as a promising target for invasive cancers

Cited by 16 publications

References 22 publications

Novel targeted therapies and immunotherapy for advanced thyroid cancers

Novel targeted therapies and immunotherapy for advanced thyroid cancers

Role of Non Receptor Tyrosine Kinases in Hematological Malignances and its Targeting by Natural Products

Context‐specific protein tyrosine kinase 6 (PTK6) signalling in prostate cancer

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