Tyrosine Kinase Receptors in Oncology

Esteban-Villarrubia, Jorge; Castillo, Jonathan; Pozas, Javier; Román-Gil, María San; Orejana-Martín, Inmaculada; Torres-Jiménez, Javier; Carrato, Alfredo; Alonso‐Gordoa, Teresa; Molina‐Cerrillo, Javier

doi:10.3390/ijms21228529

Cited by 48 publications

(39 citation statements)

References 308 publications

(344 reference statements)

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“…Chemotherapy has limited efficacy in cases of underlying liver cirrhosis, and due to intrinsic chemoresistance of most HCCs [ 4 ]. Tyrosine kinase receptors are involved in tumorigenesis; therefore, kinase inhibitors show some benefit and, to date, the multikinase inhibitors sorafenib, lenvatinib and regorafenib have been approved for the treatment of HCC [ 5 , 6 , 7 ]. However, the overall survival of the majority of HCC patients who are not eligible for curative approaches is unfavorable [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

New 3-Aryl-2-(2-thienyl)acrylonitriles with High Activity Against Hepatoma Cells

Schaller

Gosch

et al. 2021

IJMS

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New 2-(thien-2-yl)-acrylonitriles with putative kinase inhibitory activity were prepared and tested for their antineoplastic efficacy in hepatoma models. Four out of the 14 derivatives were shown to inhibit hepatoma cell proliferation at (sub-)micromolar concentrations with IC50 values below that of the clinically relevant multikinase inhibitor sorafenib, which served as a reference. Colony formation assays as well as primary in vivo examinations of hepatoma tumors grown on the chorioallantoic membrane of fertilized chicken eggs (CAM assay) confirmed the excellent antineoplastic efficacy of the new derivatives. Their mode of action included an induction of apoptotic capsase-3 activity, while no contribution of unspecific cytotoxic effects was observed in LDH-release measurements. Kinase profiling of cancer relevant protein kinases identified the two 3-aryl-2-(thien-2-yl)acrylonitrile derivatives 1b and 1c as (multi-)kinase inhibitors with a preferential activity against the VEGFR-2 tyrosine kinase. Additional bioinformatic analysis of the VEGFR-2 binding modes by docking and molecular dynamics calculations supported the experimental findings and indicated that the hydroxy group of 1c might be crucial for its distinct inhibitory potency against VEGFR-2. Forthcoming studies will further unveil the underlying mode of action of the promising new derivatives as well as their suitability as an urgently needed novel approach in HCC treatment.

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Section: Introductionmentioning

confidence: 99%

New 3-Aryl-2-(2-thienyl)acrylonitriles with High Activity Against Hepatoma Cells

Schaller

Gosch

et al. 2021

IJMS

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“…In physiological conditions, cell surface RTKs are activated when their extracellular domain is engaged with its ligand, typically a growth factor, thus inducing receptor dimerisation and tyrosine kinase activity [ 5 , 6 , 7 ]. RTKs auto-phosphorylate tyrosine residues in their cytosolic region, and engage many downstream signalling proteins, activating signal cascades that regulate cell replication, growth, differentiation, and survival [ 8 ]. Instead, in cancer cells, oncogenic alterations of RTKs (caused by mutations, genomic amplification, and chromosomal rearrangements) result in aberrant RTKs activation and downstream signal transduction, disrupting the balance between cell proliferation and cell death [ 6 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…RTKs auto-phosphorylate tyrosine residues in their cytosolic region, and engage many downstream signalling proteins, activating signal cascades that regulate cell replication, growth, differentiation, and survival [ 8 ]. Instead, in cancer cells, oncogenic alterations of RTKs (caused by mutations, genomic amplification, and chromosomal rearrangements) result in aberrant RTKs activation and downstream signal transduction, disrupting the balance between cell proliferation and cell death [ 6 , 8 ]. Since RTKs play crucial roles in cancer development, they represent molecular therapeutic targets for cancer treatment.…”

Section: Introductionmentioning

confidence: 99%

“…Since RTKs play crucial roles in cancer development, they represent molecular therapeutic targets for cancer treatment. In fact, many small molecule inhibitors have been developed for malignancies associated with mutated RTKs [ 7 , 8 , 9 , 10 ]. By targeting the ATP binding site (or an adjacent region), they specifically inhibit the tyrosine kinase function, prevent the phosphorylation of intracellular signal molecules, and block intracellular signal pathways that favour tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

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Lemur Tyrosine Kinases and Prostate Cancer: A Literature Review

Ferrari

Naponelli

Bettuzzi

2021

IJMS

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The members of the Lemur Tyrosine Kinases (LMTK1-3) subfamily constitute a group of three membrane-anchored kinases. They are known to influence a wide variety of key cellular events, often affecting cell proliferation and apoptosis. They have been discovered to be involved in cancer, in that they impact various signalling pathways that influence cell proliferation, migration, and invasiveness. Notably, in the context of genome-wide association studies, one member of the LMTK family has been identified as a candidate gene which could contribute to the development of prostate cancer. In this review, of published literature, we present evidence on the role of LMTKs in human prostate cancer and model systems, focusing on the complex network of interacting partners involved in signalling cascades that are frequently activated in prostate cancer malignancy. We speculate that the modulators of LMTK enzyme expression and activity would be of high clinical relevance for the design of innovative prostate cancer treatment.

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“…In a Phase 3 trial, llovet et al demonstrated that sorafenib, an oral multi-kinase inhibitor, delayed tumor progression and increased survival among patients with advanced HCC [8]. Sorafenib inhibits the activity of several tyrosine kinases involved in angiogenesis and tumor progression, including Hepatocellular Carcinoma Treated at the National Cancer Institute of Panama (Sorafen Study) vascular endothelial growth factor receptor 2/3 (VEGFR-2/3), platelet-derived growth factor receptor (PDGF-R) and others [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Experience with Sorafenib in Patients with Advanced Hepatocellular Carcinoma Treated at the National Cancer Institute of Panama (Sorafen Study)

Dominguez-Molina¹,

Pinto-Llerena²

2021

IJCOCR

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Sorafenib is an oral multi-kinase inhibitor that increases survival and delays tumor progression in patients with advanced hepatocarcinoma (HCC). This study aimed to determine the progression-free survival (PFS) and overall survival (OS) and to analyze OS-related factors in this population between 2014 and 2019. We performed a retrospective review of patients with advanced HCC who were treated with sorafenib at the National Cancer Institute of Panama (Instituto Oncologico Nacional de Panama -IONP) from January 2014 to December 2019. The data were collected from electronic health records of the IONP. In total, 77 patients with a mean age of 65 years were analyzed. Sixty-three percent of the patients were men, and most of them had an Eastern Cooperative Oncology Group (ECOG) performance status of 1 and had not undergone any prior treatment. Forty-four percent patients had Child-Pugh Class A. The most frequent progression site was the liver (27%), followed by the lungs. Mean PFS was 1 month, and mean OS was 3 months. The clinical benefit was 39% and Overall response rate was 3,9%; for those with stable disease, it was 35,1%, and 3,9% showed a partial response. More encouraging results were obtained from patients with higher functional statuses (ECOG status 0-1) and who were in milder stages of liver disease (Child-Pugh Class A). The most common adverse events were fatigue, hand-foot syndrome, nausea and vomiting, and arterial hypertension. The survival results assessed in our institution for patients with advanced hepatocellular carcinoma treated with sorafenib are below of those published in the literature; however, after selecting the cases with ECOG 0-1 and Child A stage, our results were more in line with those of the international literature, being the most important prognostic factors in our patients. Fatigue and hand-foot syndrome were the most common adverse events. The key to the success of this therapy lies in an adequate selection of patients.

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Tyrosine Kinase Receptors in Oncology

Cited by 48 publications

References 308 publications

New 3-Aryl-2-(2-thienyl)acrylonitriles with High Activity Against Hepatoma Cells

New 3-Aryl-2-(2-thienyl)acrylonitriles with High Activity Against Hepatoma Cells

Lemur Tyrosine Kinases and Prostate Cancer: A Literature Review

Experience with Sorafenib in Patients with Advanced Hepatocellular Carcinoma Treated at the National Cancer Institute of Panama (Sorafen Study)

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