Topical Collection "Kinases and Cancer"

Editor

Dr. Jonas Cicenas
E-Mail Website
Collection Editor
CALIPHO Group, Swiss Institute of Bioinformatics, CMU - 1, rue Michel Servet, CH-1211 Geneva 4, Switzerland
Fax: +41 22 379 58 58
Interests: breast cancer; prostate cancer; acute myeloid leukemia (AML); kinases
Special Issues and Collections in MDPI journals

Topical Collection 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
Collection Editor

Manuscript Submission Information

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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 (11 papers)

2019

Jump to: 2018, 2017, 2015, 2014, 2013

Open AccessArticle
Proteomic Analysis of Breast Cancer Resistance to the Anticancer Drug RH1 Reveals the Importance of Cancer Stem Cells
Cancers 2019, 11(7), 972; https://doi.org/10.3390/cancers11070972 - 11 Jul 2019
Abstract
Antitumor drug resistance remains a major challenge in cancer chemotherapy. Here we investigated the mechanism of acquired resistance to a novel anticancer agent RH1 designed to be activated in cancer cells by the NQO1 enzyme. Data show that in some cancer cells RH1 [...] Read more.
Antitumor drug resistance remains a major challenge in cancer chemotherapy. Here we investigated the mechanism of acquired resistance to a novel anticancer agent RH1 designed to be activated in cancer cells by the NQO1 enzyme. Data show that in some cancer cells RH1 may act in an NQO1-independent way. Differential proteomic analysis of breast cancer cells with acquired resistance to RH1 revealed changes in cell energy, amino acid metabolism and G2/M cell cycle transition regulation. Analysis of phosphoproteomics and protein kinase activity by multiplexed kinase inhibitor beads showed an increase in the activity of protein kinases involved in the cell cycle and stemness regulation and downregulation of proapoptotic kinases such as JNK in RH1-resistant cells. Suppression of JNK leads to the increase of cancer cell resistance to RH1. Moreover, resistant cells have enhanced expression of stem cell factor (SCF) and stem cell markers. Inhibition of SCF receptor c-KIT resulted in the attenuation of cancer stem cell enrichment and decreased amounts of tumor-initiating cells. RH1-resistant cells also acquire resistance to conventional therapeutics while remaining susceptible to c-KIT-targeted therapy. Data show that RH1 can be useful to treat cancers in the NQO1-independent way, and targeting of the cancer stem cells might be an effective approach for combating resistance to RH1 therapy. Full article
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Open AccessArticle
SYK Inhibition Potentiates the Effect of Chemotherapeutic Drugs on Neuroblastoma Cells In Vitro
Cancers 2019, 11(2), 202; https://doi.org/10.3390/cancers11020202 - 10 Feb 2019
Abstract
Neuroblastoma is a malignancy arising from the developing sympathetic nervous system and the most common and deadly cancer of infancy. New therapies are needed to improve the prognosis for high-risk patients and to reduce toxicity and late effects. Spleen tyrosine kinase (SYK) has [...] Read more.
Neuroblastoma is a malignancy arising from the developing sympathetic nervous system and the most common and deadly cancer of infancy. New therapies are needed to improve the prognosis for high-risk patients and to reduce toxicity and late effects. Spleen tyrosine kinase (SYK) has previously been identified as a promising drug target in various inflammatory diseases and cancers but has so far not been extensively studied as a potential therapeutic target in neuroblastoma. In this study, we observed elevated SYK gene expression in neuroblastoma compared to neural crest and benign neurofibroma. While SYK protein was detected in the majority of examined neuroblastoma tissues it was less frequently observed in neuroblastoma cell lines. Depletion of SYK by siRNA and the use of small molecule SYK inhibitors significantly reduced the cell viability of neuroblastoma cell lines expressing SYK protein. Moreover, SYK inhibition decreased ERK1/2 and Akt phosphorylation. The SYK inhibitor BAY 61-3606 enhanced the effect of different chemotherapeutic drugs. Transient expression of a constitutive active SYK variant increased the viability of neuroblastoma cells independent of endogenous SYK levels. Collectively, our findings suggest that targeting SYK in combination with conventional chemotherapy should be further evaluated as a treatment option in neuroblastoma. Full article
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2018

Jump to: 2019, 2017, 2015, 2014, 2013

Open AccessArticle
Focal Adhesion Genes Refine the Intermediate-Risk Cytogenetic Classification of Acute Myeloid Leukemia
Cancers 2018, 10(11), 436; https://doi.org/10.3390/cancers10110436 - 13 Nov 2018
Abstract
In recent years, several attempts have been made to identify novel prognostic markers in patients with intermediate-risk acute myeloid leukemia (IR-AML), to implement risk-adapted strategies. The non-receptor tyrosine kinases are proteins involved in regulation of cell growth, adhesion, migration and apoptosis. They associate [...] Read more.
In recent years, several attempts have been made to identify novel prognostic markers in patients with intermediate-risk acute myeloid leukemia (IR-AML), to implement risk-adapted strategies. The non-receptor tyrosine kinases are proteins involved in regulation of cell growth, adhesion, migration and apoptosis. They associate with metastatic dissemination in solid tumors and poor prognosis. However, their role in haematological malignancies has been scarcely studied. We hypothesized that PTK2/FAK, PTK2B/PYK2, LYN or SRC could be new prognostic markers in IR-AML. We assessed PTK2, PTK2B, LYN and SRC gene expression in a cohort of 324 patients, adults up to the age of 70, classified in the IR-AML cytogenetic group. Univariate and multivariate analyses showed that PTK2B, LYN and PTK2 gene expression are independent prognostic factors in IR-AML patients. PTK2B and LYN identify a patient subgroup with good prognosis within the cohort with non-favorable FLT3/NPM1 combined mutations. In contrast, PTK2 identifies a patient subgroup with poor prognosis within the worst prognosis cohort who display non-favorable FLT3/NPM1 combined mutations and underexpression of PTK2B or LYN. The combined use of these markers can refine the highly heterogeneous intermediate-risk subgroup of AML patients, and allow the development of risk-adapted post-remission chemotherapy protocols to improve their response to treatment. Full article
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Open AccessEditorial
Kinases and Cancer
Cancers 2018, 10(3), 63; https://doi.org/10.3390/cancers10030063 - 01 Mar 2018
Cited by 2
Abstract
Protein kinases are a large family of enzymes catalyzing protein phosphorylation. The human genome contains 518 protein kinase genes, 478 of which belong to the classical protein kinase family and 40 are atypical protein kinases [...]
Full article
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2017

Jump to: 2019, 2018, 2015, 2014, 2013

Open AccessEditorial
JNK, p38, ERK, and SGK1 Inhibitors in Cancer
Cancers 2018, 10(1), 1; https://doi.org/10.3390/cancers10010001 - 21 Dec 2017
Cited by 8
Abstract
Mitogen-activated protein kinases (MAP kinases) are a family of kinases that regulates a range of biological processes implicated in the response to growth factors like latelet-derived growth factor (PDGF), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), and stress, such as ultraviolet [...] Read more.
Mitogen-activated protein kinases (MAP kinases) are a family of kinases that regulates a range of biological processes implicated in the response to growth factors like latelet-derived growth factor (PDGF), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), and stress, such as ultraviolet irradiation, heat shock, and osmotic shock. The MAP kinase family consists of four major subfamilies of related proteins (extracellular regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), p38, and extracellular regulated kinase 5 (ERK5)) and regulates numerous cellular activities, such as apoptosis, gene expression, mitosis, differentiation, and immune responses. The deregulation of these kinases is shown to be involved in human diseases, such as cancer, immune diseases, inflammation, and neurodegenerative disorders. The awareness of the therapeutic potential of the inhibition of MAP kinases led to a thorough search for small-molecule inhibitors. Here, we discuss some of the most well-known MAP kinase inhibitors and their use in cancer research. Full article
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2015

Jump to: 2019, 2018, 2017, 2014, 2013

Open AccessReview
Targeting Cyclin-Dependent Kinases in Human Cancers: From Small Molecules to Peptide Inhibitors
Cancers 2015, 7(1), 179-237; https://doi.org/10.3390/cancers7010179 - 23 Jan 2015
Cited by 89
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 [...] Read more.
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
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2014

Jump to: 2019, 2018, 2017, 2015, 2013

Open AccessReview
Highlights of the Latest Advances in Research on CDK Inhibitors
Cancers 2014, 6(4), 2224-2242; https://doi.org/10.3390/cancers6042224 - 27 Oct 2014
Cited by 71
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 [...] Read more.
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
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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; https://doi.org/10.3390/cancers6031487 - 08 Jul 2014
Cited by 2
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 [...] Read more.
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
Open AccessReview
The Role of PI3K/Akt/mTOR Signaling in Gastric Carcinoma
Cancers 2014, 6(3), 1441-1463; https://doi.org/10.3390/cancers6031441 - 07 Jul 2014
Cited by 72
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 [...] Read more.
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
Open AccessReview
The Multifunctional Protein Kinase C-ε in Cancer Development and Progression
Cancers 2014, 6(2), 860-878; https://doi.org/10.3390/cancers6020860 - 10 Apr 2014
Cited by 26
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 [...] Read more.
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
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2013

Jump to: 2019, 2018, 2017, 2015, 2014

Open AccessArticle
Characterization of a Dual CDC7/CDK9 Inhibitor in Multiple Myeloma Cellular Models
Cancers 2013, 5(3), 901-918; https://doi.org/10.3390/cancers5030901 - 24 Jul 2013
Cited by 8
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 [...] Read more.
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
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