Editorial

4 pages, 895 KiB

Open AccessEditorial

Targeting Tyrosine Kinases in Cancer: Lessons for an Effective Targeted Therapy in the Clinic

by Adriano Angelucci

Cancers 2019, 11(4), 490; https://doi.org/10.3390/cancers11040490 - 06 Apr 2019

Cited by 6 | Viewed by 2566

The 21st century has finally seen the full achievement of targeted therapy to treat cancer with the promise of lower side effects and improved efficacy with respect to cytotoxic chemotherapeutics [...] Full article

(This article belongs to the Special Issue Tyrosine Kinase Signaling Pathways in Cancer)

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Research

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17 pages, 6891 KiB

Open AccessArticle

Combination of EGFR Inhibitor Lapatinib and MET Inhibitor Foretinib Inhibits Migration of Triple Negative Breast Cancer Cell Lines

by Aleksandra Simiczyjew, Ewelina Dratkiewicz, Marleen Van Troys, Christophe Ampe, Ilona Styczeń and Dorota Nowak

Cancers 2018, 10(9), 335; https://doi.org/10.3390/cancers10090335 - 17 Sep 2018

Cited by 25 | Viewed by 5965

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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16 pages, 2279 KiB

Open AccessFeature PaperArticle

Activation of ERBB4 in Glioblastoma Can Contribute to Increased Tumorigenicity and Influence Therapeutic Response

by Jacqueline F. Donoghue, Lauren T. Kerr, Naomi W. Alexander, Sameer A. Greenall, Anthony B. Longano, Nicholas G. Gottardo, Rong Wang, Viviane Tabar, Timothy E. Adams, Paul S. Mischel and Terrance G. Johns

Cancers 2018, 10(8), 243; https://doi.org/10.3390/cancers10080243 - 25 Jul 2018

Cited by 19 | Viewed by 4894

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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11 pages, 1776 KiB

Open AccessArticle

Responses to the Selective Bruton’s Tyrosine Kinase (BTK) Inhibitor Tirabrutinib (ONO/GS-4059) in Diffuse Large B-cell Lymphoma Cell Lines

by Ryohei Kozaki, Meike Vogler, Harriet S. Walter, Sandrine Jayne, David Dinsdale, Reiner Siebert, Martin J.S. Dyer and Toshio Yoshizawa

Cancers 2018, 10(4), 127; https://doi.org/10.3390/cancers10040127 - 23 Apr 2018

Cited by 26 | Viewed by 8027

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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12 pages, 890 KiB

Open AccessArticle

Mutations in EMT-Related Genes in ALK Positive Crizotinib Resistant Non-Small Cell Lung Cancers

by Jiacong Wei, Anthonie J. Van der Wekken, Ali Saber, Miente M. Terpstra, Ed Schuuring, Wim Timens, T. Jeroen N. Hiltermann, Harry J. M. Groen, Anke Van den Berg and Klaas Kok

Cancers 2018, 10(1), 10; https://doi.org/10.3390/cancers10010010 - 04 Jan 2018

Cited by 34 | Viewed by 4947

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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27 pages, 1462 KiB

Open AccessReview

The Emerging Role of TYRO3 as a Therapeutic Target in Cancer

by Sherri K. Smart, Eleana Vasileiadi, Xiaodong Wang, Deborah DeRyckere and Douglas K. Graham

Cancers 2018, 10(12), 474; https://doi.org/10.3390/cancers10120474 - 29 Nov 2018

Cited by 58 | Viewed by 6755

Abstract

The TAM family (TYRO3, AXL, MERTK) tyrosine kinases play roles in diverse biological processes including immune regulation, clearance of apoptotic cells, platelet aggregation, and cell proliferation, survival, and migration. While AXL and MERTK have been extensively studied, less is known about TYRO3. Recent [...] Read more.

The TAM family (TYRO3, AXL, MERTK) tyrosine kinases play roles in diverse biological processes including immune regulation, clearance of apoptotic cells, platelet aggregation, and cell proliferation, survival, and migration. While AXL and MERTK have been extensively studied, less is known about TYRO3. Recent studies revealed roles for TYRO3 in cancer and suggest TYRO3 as a therapeutic target in this context. TYRO3 is overexpressed in many types of cancer and functions to promote tumor cell survival and/or proliferation, metastasis, and resistance to chemotherapy. In addition, higher levels of TYRO3 expression have been associated with decreased overall survival in patients with colorectal, hepatocellular, and breast cancers. Here we review the physiological roles for TYRO3 and its expression and functions in cancer cells and the tumor microenvironment, with emphasis on the signaling pathways that are regulated downstream of TYRO3 and emerging roles for TYRO3 in the immune system. Translational agents that target TYRO3 are also described. Full article

(This article belongs to the Special Issue Tyrosine Kinase Signaling Pathways in Cancer)

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18 pages, 524 KiB

Open AccessReview

Recent Studies on Ponatinib in Cancers Other Than Chronic Myeloid Leukemia

by Francesca Musumeci, Chiara Greco, Giancarlo Grossi, Alessio Molinari and Silvia Schenone

Cancers 2018, 10(11), 430; https://doi.org/10.3390/cancers10110430 - 09 Nov 2018

Cited by 28 | Viewed by 5884

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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15 pages, 1556 KiB

Open AccessReview

The Cooperative Relationship between STAT5 and Reactive Oxygen Species in Leukemia: Mechanism and Therapeutic Potential

by Tian Mi, Zhengqi Wang and Kevin D. Bunting

Cancers 2018, 10(10), 359; https://doi.org/10.3390/cancers10100359 - 27 Sep 2018

Cited by 20 | Viewed by 4492

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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21 pages, 645 KiB

Open AccessReview

The Roles of Protein Tyrosine Phosphatases in Hepatocellular Carcinoma

by Yide Huang, Yafei Zhang, Lilin Ge, Yao Lin and Hang Fai Kwok

Cancers 2018, 10(3), 82; https://doi.org/10.3390/cancers10030082 - 20 Mar 2018

Cited by 34 | Viewed by 7520

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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