Special Issue "Kinases and Cancer"

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A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 March 2014)

Special Issue Editor

Guest Editor
Dr. Jonas Cicenas

CALIPHO Group, Swiss Institute of Bioinformatics, CMU - 1, rue Michel Servet, CH-1211 Geneva 4, Switzerland
Website | E-Mail
Fax: +41 22 379 58 58
Interests: breast cancer; prostate cancer; acute myeloid leukemia (AML); kinases

Special Issue Information

Dear Colleagues,

Protein phosphorylation is one of the most critical mechanisms for regulating various cellular functions. Consequently, protein kinase dysfunctions have been associated with the development of various types and subtypes of human cancers. Some examples include amplification and overexpression of the epidermal growth factor receptor (EGFR) and the ERBB2 receptor in lung and breast tumors, mutation of the BRAF oncogene in a wide range of human tumors, and the chromosomal translocation known as the Philadelphia chromosome, which results in ABL1 tyrosine kinase activation.
In the drug discovery field, despite early skepticism on the potential and selectivity of protein kinase inhibitors, enormous progress has been made. New classes of drugs, such as antibodies to receptors, and small-molecule inhibitors, were developed and tested in the clinics. The success of such drugs (e.g., imatinib and trastuzumab) encouraged development of new, second-generation drugs, which target protein kinases in cancer. Moreover, kinases have been shown to be invaluable diagnostic, prognostic, and predictive biomarkers for many types of cancers. In addition to protein kinases, lipid kinases, such as phosphatidylinositol-3-kinase (PI3K) and phosphatidylinositol-4-kinase (PI4K), have also been involved in the pathology of many tumors. In this issue of Cancers, “Kinases and Cancers”, experts are invited to contribute original research papers or review articles that will provide further insights on the various functions of kinases in cancers, and on their role as drug targets and biomarkers.

Dr. Jonas Cicenas (EMB of Cancers)
Guest Editor

Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed Open Access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 800 CHF (Swiss Francs).

Keywords

  • kinase inhibitors in cancer therapy
  • monoclonal antibodies against kinases in cancer therapy
  • kinases as oncogenes
  • kinases as tumor supressors
  • kinases as biomarkers
  • protein phosphorylation and cancer

Published Papers (6 papers)

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Research

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Open AccessArticle Comparison of Intracellular Stress Response of NCI-H526 Small Cell Lung Cancer (SCLC) Cells to Platinum(II) Cisplatin and Platinum(IV) Oxoplatin
Cancers 2014, 6(3), 1487-1499; doi:10.3390/cancers6031487
Received: 4 April 2014 / Revised: 30 June 2014 / Accepted: 2 July 2014 / Published: 8 July 2014
Cited by 1 | PDF Full-text (624 KB) | HTML Full-text | XML Full-text
Abstract
In attempts to develop an orally applicable platinum-based drug, platinum(IV) drugs which exhibit higher in vivo stability compared to the platinum(II) drug cisplatin were formulated. The first such chemotherapeutic agent, namely satraplatin, failed to receive approval. In the present work, we checked the
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In attempts to develop an orally applicable platinum-based drug, platinum(IV) drugs which exhibit higher in vivo stability compared to the platinum(II) drug cisplatin were formulated. The first such chemotherapeutic agent, namely satraplatin, failed to receive approval. In the present work, we checked the initial cellular stress response of the chemosensitive NCI-H526 small cell lung cancer (SCLC) cells by determination of the relative phosphorylation of 46 specific phosphorylation sites of 38 selected proteins in a six hours response to cisplatin (platinum(II)) or oxoplatin (platinum(IV)), respectively. Oxoplatin is considered as prodrug of cisplatin, although several findings point to differences in intracellular effects. Cisplatin induced hyperphosphorylation of p38α MAPK and AMPKα1, whereas oxoplatin treatment resulted in increased phosphorylation of a large number of signaling proteins involved in stress response/drug resistance, including JNK, GSK-3α, AMPKα1, src kinases, STATs, CHK-2 and especially focal adhesion kinase (FAK). Cisplatin exerts markedly higher cytotoxicity upon four hours short-term exposure in comparison to oxoplatin and, correspondingly, the extended initial stress response to the platinum(IV) drug oxoplatin thus is expected to increase clinical drug resistance. Induction of a substantial stress response to any prodrug of a platinum-based compound may likewise limit the effectivity of its active metabolite(s), such contributing to the failure of selected derivatized platinum complexes. Full article
(This article belongs to the Special Issue Kinases and Cancer)
Open AccessArticle Characterization of a Dual CDC7/CDK9 Inhibitor in Multiple Myeloma Cellular Models
Cancers 2013, 5(3), 901-918; doi:10.3390/cancers5030901
Received: 5 June 2013 / Revised: 4 July 2013 / Accepted: 4 July 2013 / Published: 24 July 2013
Cited by 3 | PDF Full-text (734 KB) | HTML Full-text | XML Full-text
Abstract
Two key features of myeloma cells are the deregulation of the cell cycle and the dependency on the expression of the BCL2 family of anti-apoptotic proteins. The cell division cycle 7 (CDC7) is an essential S-phase kinase and emerging CDC7 inhibitors are effective
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Two key features of myeloma cells are the deregulation of the cell cycle and the dependency on the expression of the BCL2 family of anti-apoptotic proteins. The cell division cycle 7 (CDC7) is an essential S-phase kinase and emerging CDC7 inhibitors are effective in a variety of preclinical cancer models. These compounds also inhibit CDK9 which is relevant for MCL-1 expression. The activity and mechanism of action of the dual CDC7/CDK9 inhibitor PHA-767491 was assessed in a panel of multiple myeloma cell lines, in primary samples from patients, in the presence of stromal cells and in combination with drugs used in current chemotherapeutic regimens. We report that in all conditions myeloma cells undergo cell death upon PHA-767491 treatment and we report an overall additive effect with melphalan, bortezomib and doxorubicin, thus supporting further assessment of targeting CDC7 and CDK9 in multiple myeloma. Full article
(This article belongs to the Special Issue Kinases and Cancer)

Review

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Open AccessReview Targeting Cyclin-Dependent Kinases in Human Cancers: From Small Molecules to Peptide Inhibitors
Cancers 2015, 7(1), 179-237; doi:10.3390/cancers7010179
Received: 17 December 2014 / Accepted: 12 January 2015 / Published: 23 January 2015
Cited by 16 | PDF Full-text (2383 KB) | HTML Full-text | XML Full-text
Abstract
Cyclin-dependent kinases (CDK/Cyclins) form a family of heterodimeric kinases that play central roles in regulation of cell cycle progression, transcription and other major biological processes including neuronal differentiation and metabolism. Constitutive or deregulated hyperactivity of these kinases due to amplification, overexpression or mutation
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Cyclin-dependent kinases (CDK/Cyclins) form a family of heterodimeric kinases that play central roles in regulation of cell cycle progression, transcription and other major biological processes including neuronal differentiation and metabolism. Constitutive or deregulated hyperactivity of these kinases due to amplification, overexpression or mutation of cyclins or CDK, contributes to proliferation of cancer cells, and aberrant activity of these kinases has been reported in a wide variety of human cancers. These kinases therefore constitute biomarkers of proliferation and attractive pharmacological targets for development of anticancer therapeutics. The structural features of several of these kinases have been elucidated and their molecular mechanisms of regulation characterized in depth, providing clues for development of drugs and inhibitors to disrupt their function. However, like most other kinases, they constitute a challenging class of therapeutic targets due to their highly conserved structural features and ATP-binding pocket. Notwithstanding, several classes of inhibitors have been discovered from natural sources, and small molecule derivatives have been synthesized through rational, structure-guided approaches or identified in high throughput screens. The larger part of these inhibitors target ATP pockets, but a growing number of peptides targeting protein/protein interfaces are being proposed, and a small number of compounds targeting allosteric sites have been reported. Full article
(This article belongs to the Special Issue Kinases and Cancer)
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Open AccessReview Highlights of the Latest Advances in Research on CDK Inhibitors
Cancers 2014, 6(4), 2224-2242; doi:10.3390/cancers6042224
Received: 25 July 2014 / Revised: 30 September 2014 / Accepted: 14 October 2014 / Published: 27 October 2014
Cited by 23 | PDF Full-text (637 KB) | HTML Full-text | XML Full-text
Abstract
Uncontrolled proliferation is the hallmark of cancer and other proliferative disorders and abnormal cell cycle regulation is, therefore, common in these diseases. Cyclin-dependent kinases (CDKs) play a crucial role in the control of the cell cycle and proliferation. These kinases are frequently deregulated
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Uncontrolled proliferation is the hallmark of cancer and other proliferative disorders and abnormal cell cycle regulation is, therefore, common in these diseases. Cyclin-dependent kinases (CDKs) play a crucial role in the control of the cell cycle and proliferation. These kinases are frequently deregulated in various cancers, viral infections, neurodegenerative diseases, ischemia and some proliferative disorders. This led to a rigorous pursuit for small-molecule CDK inhibitors for therapeutic uses. Early efforts to block CDKs with nonselective CDK inhibitors led to little specificity and efficacy but apparent toxicity, but the recent advance of selective CDK inhibitors allowed the first successful efforts to target these kinases for the therapies of several diseases. Major ongoing efforts are to develop CDK inhibitors as monotherapies and rational combinations with chemotherapy and other targeted drugs. Full article
(This article belongs to the Special Issue Kinases and Cancer)
Open AccessReview The Role of PI3K/Akt/mTOR Signaling in Gastric Carcinoma
Cancers 2014, 6(3), 1441-1463; doi:10.3390/cancers6031441
Received: 14 April 2014 / Revised: 24 June 2014 / Accepted: 26 June 2014 / Published: 7 July 2014
Cited by 23 | PDF Full-text (802 KB) | HTML Full-text | XML Full-text
Abstract
The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is one of the key signaling pathways induced by various receptor-tyrosine kinases. Accumulating evidence shows that this pathway is an important promoter of cell growth, metabolism, survival, metastasis, and resistance to chemotherapy. Genetic alterations
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The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is one of the key signaling pathways induced by various receptor-tyrosine kinases. Accumulating evidence shows that this pathway is an important promoter of cell growth, metabolism, survival, metastasis, and resistance to chemotherapy. Genetic alterations in the PI3K/Akt/mTOR pathway in gastric carcinoma have often been demonstrated. Many kinds of molecular targeting therapies are currently undergoing clinical testing in patients with solid tumors. However, with the exception of the ErbB2-targeting antibody, targeting agents, including PI3K/Akt/mTOR inhibitors, have not been approved for treatment of patients with gastric carcinoma. This review summarizes the current knowledge on PI3K/Akt/mTOR signaling in the pathogenesis of gastric carcinoma and the possible therapeutic targets for gastric carcinoma. Improved knowledge of the PI3K/Akt/mTOR pathway in gastric carcinoma will be useful in understanding the mechanisms of tumor development and for identifying ideal targets of anticancer therapy for gastric carcinoma. Full article
(This article belongs to the Special Issue Kinases and Cancer)
Open AccessReview The Multifunctional Protein Kinase C-ε in Cancer Development and Progression
Cancers 2014, 6(2), 860-878; doi:10.3390/cancers6020860
Received: 26 February 2014 / Revised: 27 March 2014 / Accepted: 1 April 2014 / Published: 10 April 2014
Cited by 9 | PDF Full-text (656 KB) | HTML Full-text | XML Full-text
Abstract
The protein kinase C (PKC) family proteins are important signal transducers and have long been the focus of cancer research. PKCɛ, a member of this family, is overexpressed in most solid tumors and plays critical roles in different processes that lead to cancer
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The protein kinase C (PKC) family proteins are important signal transducers and have long been the focus of cancer research. PKCɛ, a member of this family, is overexpressed in most solid tumors and plays critical roles in different processes that lead to cancer development. Studies using cell lines and animal models demonstrated the transforming potential of PKCɛ. While earlier research established the survival functions of PKCɛ, recent studies revealed its role in cell migration, invasion and cancer metastasis. PKCɛ has also been implicated in epithelial to mesenchymal transition (EMT), which may be the underlying mechanism by which it contributes to cell motility. In addition, PKCɛ affects cell-extracellular matrix (ECM) interactions by direct regulation of the cytoskeletal elements. Recent studies have also linked PKCɛ signaling to cancer stem cell functioning. This review focuses on the role of PKCɛ in different processes that lead to cancer development and progression. We also discussed current literatures on the pursuit of PKCɛ as a target for cancer therapy. Full article
(This article belongs to the Special Issue Kinases and Cancer)
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