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Cancers
Special Issues
Kinase Signaling in Cancer
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Kinase Signaling in Cancer

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

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 11443

Special Issue Editors

Dr. Markku Varjosalo

E-Mail Website
Guest Editor
Institute of Biotechnology & HiLIFE, University of Helsinki, Biocenter 3, Viikinkaari 1, FI00790 Helsinki, Finland
Interests: protein kinases; oncogenic gene fusions; cancer; drug discovery; systems biology; systems pathology
Prof. Dr. Kaisa Lehti

E-Mail Website
Guest Editor
Department of Biomedical Laboratory Science, Norges Teknisk-Naturvitenskapelige Universitet, Trondheim, Norway
Interests: protein kinases; oncogenic gene fusions; cancer; drug discovery; systems biology; systems pathology

Special Issue Information

Dear Colleagues,

At any given time in any given cell, multiple types of molecular networks are concurrently active. An important feature of these networks is the multiple reversible reactions of protein phosphorylation (catalyzed by protein kinases) and dephosphorylation (catalyzed by protein phosphatases). Protein kinases (PKs) are one of the largest families of genes in eukaryotes, and approximately 2% of all human genes have protein kinase domain(s). Protein kinases mediate most of the signal transduction events in cells by the phosphorylation of specific substrates—modifying their activity, cellular location, and/or association with other proteins. Protein phosphorylation plays a crucial role in biological functions, and controls nearly every cellular process, including metabolism, gene transcription and translation, cell-cycle progression, cytoskeletal rearrangement, protein–protein interactions, protein stability, cell movement, and apoptosis. Therefore, it is not surprising that approximately 20% of kinase genes are estimated to function as cancer genes. In addition to harboring activating/inactivating somatic point mutations, PKs account currently for >10% of all human fusion genes found in cancer.

Kinase-activity-modulating kinase inhibitors of monoclonal antibodies constitute a rapidly growing therapeutic armamentarium. The ongoing efforts to identify the exact molecular mechanisms and pathobiology of these kinase mutations is crucial to cancer drug development.

This Special Issue of Cancers provides a collection of new research articles and timely reviews on the different protein kinase mutations in cancer, the state-of-the art analysis methods to study them, and the current status of kinase-targeting cancer drug therapies.

Dr. Markku Varjosalo
Prof. Dr. Kaisa Lehti
Guest Editors

Manuscript Submission Information

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. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short 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 thoroughly refereed through a single-blind 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 semimonthly 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 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • protein kinases
  • protein phosphorylation
  • gene fusions
  • human cancer
  • kinase-targeted cancer therapies
  • cellular signaling

Published Papers (6 papers)

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Research

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25 pages, 19126 KiB  
Article
The Impact of ETV6-NTRK3 Oncogenic Gene Fusions on Molecular and Signaling Pathway Alterations
by Matias Kinnunen, Xiaonan Liu, Elina Niemelä, Tiina Öhman, Lisa Gawriyski, Kari Salokas, Salla Keskitalo and Markku Varjosalo
Cancers 2023, 15(17), 4246; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15174246 - 24 Aug 2023
Cited by 3 | Viewed by 1272
Abstract
Chromosomal translocations creating fusion genes are common cancer drivers. The oncogenic ETV6-NTRK3 (EN) gene fusion joins the sterile alpha domain of the ETV6 transcription factor with the tyrosine kinase domain of the neurotrophin-3 receptor NTRK3. Four EN variants with alternating break points have [...] Read more.
Chromosomal translocations creating fusion genes are common cancer drivers. The oncogenic ETV6-NTRK3 (EN) gene fusion joins the sterile alpha domain of the ETV6 transcription factor with the tyrosine kinase domain of the neurotrophin-3 receptor NTRK3. Four EN variants with alternating break points have since been detected in a wide range of human cancers. To provide molecular level insight into EN oncogenesis, we employed a proximity labeling mass spectrometry approach to define the molecular context of the fusions. We identify in total 237 high-confidence interactors, which link EN fusions to several key signaling pathways, including ERBB, insulin and JAK/STAT. We then assessed the effects of EN variants on these pathways, and showed that the pan NTRK inhibitor Selitrectinib (LOXO-195) inhibits the oncogenic activity of EN2, the most common variant. This systems-level analysis defines the molecular framework in which EN oncofusions operate to promote cancer and provides some mechanisms for therapeutics. Full article
(This article belongs to the Special Issue Kinase Signaling in Cancer)
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Review

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28 pages, 4071 KiB  
Review
CMGC Kinases in Health and Cancer
by Iftekhar Chowdhury, Giovanna Dashi and Salla Keskitalo
Cancers 2023, 15(15), 3838; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15153838 - 28 Jul 2023
Cited by 1 | Viewed by 1209
Abstract
CMGC kinases, encompassing cyclin-dependent kinases (CDKs), mitogen-activated protein kinases (MAPKs), glycogen synthase kinases (GSKs), and CDC-like kinases (CLKs), play pivotal roles in cellular signaling pathways, including cell cycle regulation, proliferation, differentiation, apoptosis, and gene expression regulation. The dysregulation and aberrant activation of these [...] Read more.
CMGC kinases, encompassing cyclin-dependent kinases (CDKs), mitogen-activated protein kinases (MAPKs), glycogen synthase kinases (GSKs), and CDC-like kinases (CLKs), play pivotal roles in cellular signaling pathways, including cell cycle regulation, proliferation, differentiation, apoptosis, and gene expression regulation. The dysregulation and aberrant activation of these kinases have been implicated in cancer development and progression, making them attractive therapeutic targets. In recent years, kinase inhibitors targeting CMGC kinases, such as CDK4/6 inhibitors and BRAF/MEK inhibitors, have demonstrated clinical success in treating specific cancer types. However, challenges remain, including resistance to kinase inhibitors, off-target effects, and the need for better patient stratification. This review provides a comprehensive overview of the importance of CMGC kinases in cancer biology, their involvement in cellular signaling pathways, protein–protein interactions, and the current state of kinase inhibitors targeting these kinases. Furthermore, we discuss the challenges and future perspectives in targeting CMGC kinases for cancer therapy, including potential strategies to overcome resistance, the development of more selective inhibitors, and novel therapeutic approaches, such as targeting protein–protein interactions, exploiting synthetic lethality, and the evolution of omics in the study of the human kinome. As our understanding of the molecular mechanisms and protein–protein interactions involving CMGC kinases expands, so too will the opportunities for the development of more selective and effective therapeutic strategies for cancer treatment. Full article
(This article belongs to the Special Issue Kinase Signaling in Cancer)
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17 pages, 1080 KiB  
Review
Therapeutic Potential of Protein Tyrosine Kinase 6 in Colorectal Cancer
by Samanta Jerin, Amanda J. Harvey and Annabelle Lewis
Cancers 2023, 15(14), 3703; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15143703 - 21 Jul 2023
Cited by 2 | Viewed by 1485
Abstract
PTK6, a non-receptor tyrosine kinase, modulates the pathogenesis of breast and prostate cancers and is recognized as a biomarker of breast cancer prognosis. There are over 30 known substrates of PTK6, including signal transducers, transcription factors, and RNA-binding proteins. Many of these substrates [...] Read more.
PTK6, a non-receptor tyrosine kinase, modulates the pathogenesis of breast and prostate cancers and is recognized as a biomarker of breast cancer prognosis. There are over 30 known substrates of PTK6, including signal transducers, transcription factors, and RNA-binding proteins. Many of these substrates are known drivers of other cancer types, such as colorectal cancer. Colon and rectal tumors also express higher levels of PTK6 than the normal intestine suggesting a potential role in tumorigenesis. However, the importance of PTK6 in colorectal cancer remains unclear. PTK6 inhibitors such as XMU-MP-2 and Tilfrinib have demonstrated potency and selectivity in breast cancer cells when used in combination with chemotherapy, indicating the potential for PTK6 targeted therapy in cancer. However, most of these inhibitors are yet to be tested in other cancer types. Here, we discuss the current understanding of the function of PTK6 in normal intestinal cells compared with colorectal cancer cells. We review existing PTK6 targeting therapeutics and explore the possibility of PTK6 inhibitory therapy for colorectal cancer. Full article
(This article belongs to the Special Issue Kinase Signaling in Cancer)
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27 pages, 2914 KiB  
Review
Decoding Oncofusions: Unveiling Mechanisms, Clinical Impact, and Prospects for Personalized Cancer Therapies
by Kari Salokas, Giovanna Dashi and Markku Varjosalo
Cancers 2023, 15(14), 3678; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15143678 - 19 Jul 2023
Cited by 2 | Viewed by 1618
Abstract
Cancer-associated gene fusions, also known as oncofusions, have emerged as influential drivers of oncogenesis across a diverse range of cancer types. These genetic events occur via chromosomal translocations, deletions, and inversions, leading to the fusion of previously separate genes. Due to the drastic [...] Read more.
Cancer-associated gene fusions, also known as oncofusions, have emerged as influential drivers of oncogenesis across a diverse range of cancer types. These genetic events occur via chromosomal translocations, deletions, and inversions, leading to the fusion of previously separate genes. Due to the drastic nature of these mutations, they often result in profound alterations of cellular behavior. The identification of oncofusions has revolutionized cancer research, with advancements in sequencing technologies facilitating the discovery of novel fusion events at an accelerated pace. Oncofusions exert their effects through the manipulation of critical cellular signaling pathways that regulate processes such as proliferation, differentiation, and survival. Extensive investigations have been conducted to understand the roles of oncofusions in solid tumors, leukemias, and lymphomas. Large-scale initiatives, including the Cancer Genome Atlas, have played a pivotal role in unraveling the landscape of oncofusions by characterizing a vast number of cancer samples across different tumor types. While validating the functional relevance of oncofusions remains a challenge, even non-driver mutations can hold significance in cancer treatment. Oncofusions have demonstrated potential value in the context of immunotherapy through the production of neoantigens. Their clinical importance has been observed in both treatment and diagnostic settings, with specific fusion events serving as therapeutic targets or diagnostic markers. However, despite the progress made, there is still considerable untapped potential within the field of oncofusions. Further research and validation efforts are necessary to understand their effects on a functional basis and to exploit the new targeted treatment avenues offered by oncofusions. Through further functional and clinical studies, oncofusions will enable the advancement of precision medicine and the drive towards more effective and specific treatments for cancer patients. Full article
(This article belongs to the Special Issue Kinase Signaling in Cancer)
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21 pages, 2242 KiB  
Review
Regulation of Kinase Signaling Pathways by α6β4-Integrins and Plectin in Prostate Cancer
by Saara Koivusalo, Anette Schmidt, Aki Manninen and Tomasz Wenta
Cancers 2023, 15(1), 149; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15010149 - 27 Dec 2022
Cited by 3 | Viewed by 2219
Abstract
Hemidesmosomes (HDs) are adhesive structures that ensure stable anchorage of cells to the basement membrane. They are formed by α6β4-integrin heterodimers and linked to intermediate filaments via plectin. It has been reported that one of the most common events during the pathogenesis of [...] Read more.
Hemidesmosomes (HDs) are adhesive structures that ensure stable anchorage of cells to the basement membrane. They are formed by α6β4-integrin heterodimers and linked to intermediate filaments via plectin. It has been reported that one of the most common events during the pathogenesis of prostate cancer (PCa) is the loss of HD organization. While the expression levels of β4-integrins are strongly reduced, the expression levels of α6-integrins and plectin are maintained or even elevated, and seem to promote tumorigenic properties of PCa cells, such as proliferation, invasion, metastasis, apoptosis- and drug-resistance. In this review, we discuss the potential mechanisms of how HD components might contribute to various cellular signaling pathways to promote prostate carcinogenesis. Moreover, we summarize the current knowledge on the involvement of α6β4-integrins and plectin in PCa initiation and progression. Full article
(This article belongs to the Special Issue Kinase Signaling in Cancer)
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33 pages, 1170 KiB  
Review
Kinase Inhibitors in the Treatment of Ovarian Cancer: Current State and Future Promises
by Aikaterini Skorda, Marie Lund Bay, Sampsa Hautaniemi, Alexandra Lahtinen and Tuula Kallunki
Cancers 2022, 14(24), 6257; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14246257 - 19 Dec 2022
Cited by 6 | Viewed by 2921
Abstract
Ovarian cancer is the deadliest gynecological cancer, the high-grade serous ovarian carcinoma (HGSC) being its most common and most aggressive form. Despite the latest therapeutical advancements following the introduction of vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors and poly-ADP-ribose-polymerase (PARP) inhibitors [...] Read more.
Ovarian cancer is the deadliest gynecological cancer, the high-grade serous ovarian carcinoma (HGSC) being its most common and most aggressive form. Despite the latest therapeutical advancements following the introduction of vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors and poly-ADP-ribose-polymerase (PARP) inhibitors to supplement the standard platinum- and taxane-based chemotherapy, the expected overall survival of HGSC patients has not improved significantly from the five-year rate of 42%. This calls for the development and testing of more efficient treatment options. Many oncogenic kinase-signaling pathways are dysregulated in HGSC. Since small-molecule kinase inhibitors have revolutionized the treatment of many solid cancers due to the generality of the increased activation of protein kinases in carcinomas, it is reasonable to evaluate their potential against HGSC. Here, we present the latest concluded and on-going clinical trials on kinase inhibitors in HGSC, as well as the recent work concerning ovarian cancer patient organoids and xenograft models. We discuss the potential of kinase inhibitors as personalized treatments, which would require comprehensive assessment of the biological mechanisms underlying tumor spread and chemoresistance in individual patients, and their connection to tumor genome and transcriptome to establish identifiable subgroups of patients who are most likely to benefit from a given therapy. Full article
(This article belongs to the Special Issue Kinase Signaling in Cancer)
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