Special Issue "Tyrosine Kinase Signaling Pathways in Cancer"

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

Deadline for manuscript submissions: closed (15 September 2018)

Special Issue Editor

Guest Editor
Dr. Adriano Angelucci

Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, L’Aquila, Italy
Website | E-Mail
Interests: Cell Pathology; Cancer Progression; Cancer Metastasis; Targeted Therapy; Tyrosine Kinase Inhibitors

Special Issue Information

Dear Colleagues,

Protein Tyrosine Kinases (PTKs) represent the most studied topic in therapeutic oncology with several thousand of new publications per year. The interest in PTKs is due to their central role in the growth of nearly every cancer type. The early finding of BCR-ABL as effective target in curing chronic myeloid leukemia has opened a new era of the clinic oncology with the promise of non-toxic, manageable and highly specific therapies.

In the last few decades, the use of small molecules and antibodies as PTK inhibitors has confirmed that PTKs are the main drivers of fundamental processes in cancer initiation and progression, including self-sustained proliferation, migration, invasion and angiogenesis. At the same time, PTK targeted therapies have frequently produced in clinic trials unmet expectation, suggesting a lack of knowledge about the molecular control of oncogenic activation of PTKs.

The nearly one hundred of the known PTKs form a highly interconnected cellular signaling circuits that regulate in a pleiotropic and redundant manner the normal cellular communication and maintenance of homeostasis. In addition, during oncogenic transformation and progression, PTKs contribute to the aberrant phenotype and genotype through various mechanisms including enhanced expression, mutation and autocrine stimulation. In this landscape, strategies to inhibit PTKs in cancer offer still several open questions: The definition of driver and passenger PTK signaling pathways; the grade of selectivity of the PTK inhibitor to be used; the blockade of alternative/resistance PTK signaling pathways; the identification of personalized “kinome” signatures.

In this Special Issue, authors discuss the update information about PTK signaling circuits and the aberrant mechanisms associated with their oncogenic switch. Development of drugs directed against new PTK targets is also being explored. The critical evaluation of the current knowledge about PTKs is fundamental for the refinement of the current clinical therapeutic protocols and the establishment of future precision medicine.

Dr. Adriano Angelucci
Guest Editor

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 papers will be 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 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 1000 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.

Published Papers (7 papers)

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Research

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Open AccessArticle Combination of EGFR Inhibitor Lapatinib and MET Inhibitor Foretinib Inhibits Migration of Triple Negative Breast Cancer Cell Lines
Cancers 2018, 10(9), 335; https://doi.org/10.3390/cancers10090335
Received: 24 July 2018 / Revised: 10 September 2018 / Accepted: 14 September 2018 / Published: 17 September 2018
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Abstract
Triple-negative breast cancer (TNBC) is the most challenging subtype to treat due to the lack of estrogen receptor, progesterone receptor, and HER2 expression, which excludes the usage of directed targeted therapy against them. Promising therapeutic targets are the hepatocyte growth factor receptor (MET)
[...] Read more.
Triple-negative breast cancer (TNBC) is the most challenging subtype to treat due to the lack of estrogen receptor, progesterone receptor, and HER2 expression, which excludes the usage of directed targeted therapy against them. Promising therapeutic targets are the hepatocyte growth factor receptor (MET) and epidermal growth factor receptor (EGFR), which expression is frequently elevated in TNBC. Inhibitors of these receptors used as monotherapy are often ineffective. Due to that, we studied the efficacy of combined therapy targeting MET and EGFR simultaneously. Two TNBC cell lines were treated with lapatinib (a dual EGFR and HER2 inhibitor), foretinib (a MET inhibitor), or a combination of the two. After the inhibitors treatment, we verified the cell viability (XTT assay), distribution of the cell cycle phases, the activation of signaling pathways (Western blotting), distribution of invadopodia, fluorescent gelatin digestion (immunofluorescence), and the invasion capacity of cells. A combination of foretinib and lapatinib effectively reduced the viability of examined cells, led to G2/M arrest and reduction of pAKT. There was also a decreasein number of invadopodia formed by cells, their ability to digest gelatin and reduction of cells migration/invasion capacity. Therapy targeting of both EGFR and MET receptors was much more effective against tested cells than monotherapy. We selected a combination of drugs that could be successfully used against this breast cancer subtype. Full article
(This article belongs to the Special Issue Tyrosine Kinase Signaling Pathways in Cancer)
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Open AccessFeature PaperArticle Activation of ERBB4 in Glioblastoma Can Contribute to Increased Tumorigenicity and Influence Therapeutic Response
Cancers 2018, 10(8), 243; https://doi.org/10.3390/cancers10080243
Received: 12 June 2018 / Revised: 17 July 2018 / Accepted: 18 July 2018 / Published: 25 July 2018
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Abstract
Glioblastoma (GBM) is often resistant to conventional and targeted therapeutics. ErbB2 Receptor Tyrosine Kinase 4 (ERBB4) is expressed throughout normal brain and is an oncogene in several pediatric brain cancers; therefore, we investigated ERBB4 as a prognostic marker and therapeutic target in GBM.
[...] Read more.
Glioblastoma (GBM) is often resistant to conventional and targeted therapeutics. ErbB2 Receptor Tyrosine Kinase 4 (ERBB4) is expressed throughout normal brain and is an oncogene in several pediatric brain cancers; therefore, we investigated ERBB4 as a prognostic marker and therapeutic target in GBM. Using RT-qPCR, we quantified mRNA encoding total ERBB4 and known ERBB4 variants in GBM and non-neoplastic normal brain (NNB) samples. Using immunohistochemistry, we characterized the localization of total and phosphorylated ERBB4 (p-ERBB4) and EGFR protein in archived GBM samples and assessed their association with patient survival. Furthermore, we evaluated the effect of ERBB4 phosphorylation on angiogenesis and tumorigenicity in GBM xenograft models. Total ERBB4 mRNA was significantly lower in GBM than NNB samples, with the juxtamembrane JM-a and cytoplasmic CYT-2 variants predominating. ERBB4 protein was ubiquitously expressed in GBM but was not associated with patient survival. However, high p-ERBB4 in 11% of archived GBM samples, independent of p-EGFR, was associated with shorter patient survival (12.0 ± 3.2 months) than was no p-ERBB4 (22.5 ± 9.5 months). Increased ERBB4 activation was also associated with increased proliferation, angiogenesis, tumorigenicity and reduced sensitivity to anti-EGFR treatment in xenograft models. Despite low ERBB4 mRNA in GBM, the functional effects of increased ERBB4 activation identify ERBB4 as a potential prognostic and therapeutic target. Full article
(This article belongs to the Special Issue Tyrosine Kinase Signaling Pathways in Cancer)
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Open AccessArticle Responses to the Selective Bruton’s Tyrosine Kinase (BTK) Inhibitor Tirabrutinib (ONO/GS-4059) in Diffuse Large B-cell Lymphoma Cell Lines
Cancers 2018, 10(4), 127; https://doi.org/10.3390/cancers10040127
Received: 15 March 2018 / Revised: 13 April 2018 / Accepted: 20 April 2018 / Published: 23 April 2018
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Abstract
Bruton’s tyrosine kinase (BTK) is a key regulator of the B-cell receptor signaling pathway, and aberrant B-cell receptor (BCR) signaling has been implicated in the survival of malignant B-cells. However, responses of the diffuse large B-cell lymphoma (DLBCL) to inhibitors of BTK (BTKi)
[...] Read more.
Bruton’s tyrosine kinase (BTK) is a key regulator of the B-cell receptor signaling pathway, and aberrant B-cell receptor (BCR) signaling has been implicated in the survival of malignant B-cells. However, responses of the diffuse large B-cell lymphoma (DLBCL) to inhibitors of BTK (BTKi) are infrequent, highlighting the need to identify mechanisms of resistance to BTKi as well as predictive biomarkers. We investigated the response to the selective BTKi, tirabrutinib, in a panel of 64 hematopoietic cell lines. Notably, only six cell lines were found to be sensitive. Although activated B-cell type DLBCL cells were most sensitive amongst all cell types studied, sensitivity to BTKi did not correlate with the presence of activating mutations in the BCR pathway. To improve efficacy of tirabrutinib, we investigated combination strategies with 43 drugs inhibiting 34 targets in six DLBCL cell lines. Based on the results, an activated B-cell-like (ABC)-DLBCL cell line, TMD8, was the most sensitive cell line to those combinations, as well as tirabrutinib monotherapy. Furthermore, tirabrutinib in combination with idelalisib, palbociclib, or trametinib was more effective in TMD8 with acquired resistance to tirabrutinib than in the parental cells. These targeted agents might be usefully combined with tirabrutinib in the treatment of ABC-DLBCL. Full article
(This article belongs to the Special Issue Tyrosine Kinase Signaling Pathways in Cancer)
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Open AccessArticle Mutations in EMT-Related Genes in ALK Positive Crizotinib Resistant Non-Small Cell Lung Cancers
Received: 4 December 2017 / Revised: 22 December 2017 / Accepted: 29 December 2017 / Published: 4 January 2018
Cited by 2 | PDF Full-text (890 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Crizotinib is an effective drug for patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC), but upon treatment, the tumors inevitably become crizotinib resistant in time. The resistance mechanisms are only partly understood. In this study, we aim to identify gene mutations
[...] Read more.
Crizotinib is an effective drug for patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC), but upon treatment, the tumors inevitably become crizotinib resistant in time. The resistance mechanisms are only partly understood. In this study, we aim to identify gene mutations associated with resistance in ALKpositive advanced non-squamous NSCLC treated with crizotinib. Four ALK positive patients with progressive disease following crizotinib treatment were identified with paired pre- and post-crizotinib tumor tissue from our previously published cohort. Somatic variants in these samples were detected by whole exome sequencing. In one of the four patients, an ALK-resistance associated mutation was identified. In the other three patients, no ALK-resistance associated mutations were present. In these patients we identified 89 relevant somatic mutations in 74 genes that were specific to the resistant tumors. These genes were enriched in 15 pathways. Four pathways, were related to epithelial-mesenchymal transition (EMT): proteoglycans in cancer, HIF-1 signaling, FoxO signaling pathway, and ECM-receptor interaction. Analysis of other EMT-related pathways revealed three additional genes with mutations specific to the crizotinib-resistant tumor samples. The enrichment of mutations in genes associated with EMT-related pathways indicates that loss of epithelial differentiation may represent a relevant resistance mechanism for crizotinib. Full article
(This article belongs to the Special Issue Tyrosine Kinase Signaling Pathways in Cancer)
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Review

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Open AccessReview Recent Studies on Ponatinib in Cancers Other Than Chronic Myeloid Leukemia
Cancers 2018, 10(11), 430; https://doi.org/10.3390/cancers10110430
Received: 5 September 2018 / Revised: 24 October 2018 / Accepted: 7 November 2018 / Published: 9 November 2018
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Abstract
Ponatinib is a third line drug for the treatment of chronic myeloid leukemia patients, especially those that develop the gatekeeper mutation T315I, which is resistant to the first and the second line drugs imatinib, nilotinib, dasatinib and bosutinib. The compound was first identified
[...] Read more.
Ponatinib is a third line drug for the treatment of chronic myeloid leukemia patients, especially those that develop the gatekeeper mutation T315I, which is resistant to the first and the second line drugs imatinib, nilotinib, dasatinib and bosutinib. The compound was first identified as a pan Bcr-Abl and Src kinase inhibitor. Further studies have indicated that it is a multitargeted inhibitor that is active on FGFRs, RET, AKT, ERK1/2, KIT, MEKK2 and other kinases. For this reason, the compound has been evaluated on several cancers in which these kinases play important roles, including thyroid, breast, ovary and lung cancer, neuroblastoma, rhabdoid tumours and in myeloproliferative disorders. Ponatinib is also being tested in clinical trials to evaluate its activity in FLT3-ITD acute myelogenous leukemia, head and neck cancers, certain type of lung cancer, gastrointestinal stromal tumours and other malignancies. In this review we report the most recent preclinical and clinical studies on ponatinib in cancers other than CML, with the aim of giving a complete overview of this interesting compound. Full article
(This article belongs to the Special Issue Tyrosine Kinase Signaling Pathways in Cancer)
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Open AccessReview The Cooperative Relationship between STAT5 and Reactive Oxygen Species in Leukemia: Mechanism and Therapeutic Potential
Cancers 2018, 10(10), 359; https://doi.org/10.3390/cancers10100359
Received: 30 August 2018 / Revised: 21 September 2018 / Accepted: 24 September 2018 / Published: 27 September 2018
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Abstract
Reactive oxygen species (ROS) are now recognized as important second messengers with roles in many aspects of signaling during leukemogenesis. They serve as critical cell signaling molecules that regulate the activity of various enzymes including tyrosine phosphatases. ROS can induce inactivation of tyrosine
[...] Read more.
Reactive oxygen species (ROS) are now recognized as important second messengers with roles in many aspects of signaling during leukemogenesis. They serve as critical cell signaling molecules that regulate the activity of various enzymes including tyrosine phosphatases. ROS can induce inactivation of tyrosine phosphatases, which counteract the effects of tyrosine kinases. ROS increase phosphorylation of many proteins including signal transducer and activator of transcription-5 (STAT5) via Janus kinases (JAKs). STAT5 is aberrantly activated through phosphorylation in many types of cancer and this constitutive activation is associated with cell survival, proliferation, and self-renewal. Such leukemic activation of STAT5 is rarely caused by mutation of the STAT5 gene itself but instead by overactive mutant receptors with tyrosine kinase activity as well as JAK, SRC family protein tyrosine kinases (SFKs), and Abelson murine leukemia viral oncogene homolog (ABL) kinases. Interestingly, STAT5 suppresses transcription of several genes encoding antioxidant enzymes while simultaneously enhancing transcription of NADPH oxidase. By doing so, STAT5 activation promotes an overall elevation of ROS level, which acts as a feed-forward loop, especially in high risk Fms-related tyrosine kinase 3 (FLT3) mutant leukemia. Therefore, efforts have been made recently to target ROS in cancer cells. Drugs that are able to either quench ROS production or inversely augment ROS-related signaling pathways both have potential as cancer therapies and may afford some selectivity by activating feedback inhibition of the ROS-STAT5 kinome. This review summarizes the cooperative relationship between ROS and STAT5 and explores the pros and cons of emerging ROS-targeting therapies that are selective for leukemia characterized by persistent STAT5 phosphorylation. Full article
(This article belongs to the Special Issue Tyrosine Kinase Signaling Pathways in Cancer)
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Open AccessReview The Roles of Protein Tyrosine Phosphatases in Hepatocellular Carcinoma
Received: 8 January 2018 / Revised: 12 March 2018 / Accepted: 15 March 2018 / Published: 20 March 2018
Cited by 2 | PDF Full-text (645 KB) | HTML Full-text | XML Full-text
Abstract
The protein tyrosine phosphatase (PTP) family is involved in multiple cellular functions and plays an important role in various pathological and physiological processes. In many chronic diseases, for example cancer, PTP is a potential therapeutic target for cancer treatment. In the last two
[...] Read more.
The protein tyrosine phosphatase (PTP) family is involved in multiple cellular functions and plays an important role in various pathological and physiological processes. In many chronic diseases, for example cancer, PTP is a potential therapeutic target for cancer treatment. In the last two decades, dozens of PTP inhibitors which specifically target individual PTP molecules were developed as therapeutic agents. Hepatocellular carcinoma (HCC) is one of the most common malignant tumors and is the second most lethal cancer worldwide due to a lack of effective therapies. Recent studies have unveiled both oncogenic and tumor suppressive functions of PTP in HCC. Here, we review the current knowledge on the involvement of PTP in HCC and further discuss the possibility of targeting PTP in HCC. Full article
(This article belongs to the Special Issue Tyrosine Kinase Signaling Pathways in Cancer)
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