Kinase Signaling and Kinase Targeted Therapies on Cancer: Advances, Challenges, and Future Direction

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cell Signaling".

Deadline for manuscript submissions: closed (30 June 2022) | Viewed by 10678

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Guest Editor
Istituto di Endocrinologia e Oncologia Sperimentale del CNR, Dipartimento di Medicina Molecolare e Biotecnologie mediche, Università degli Studi di Napoli Federico II, Via Pansini 5, 80131 Napoli, Italy
Interests: cancer; kinase inhibitor; target therapy; signal transduction; cell cycle; mitogenesis; survival; resistance
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Special Issue Information

Dear Colleagues,

The human genome encodes 538 protein kinases that transfer a γ-phosphate group from ATP to serine, threonine, or tyrosine residues. Transferring γ-phosphate onto diverse substrates enables kinases to regulate key cellular functions. As many human diseases result from the mutation and overexpression of kinases, targeting of this enzyme class symbolizes an important strategy for drug development. Many of these kinases are associated with human cancer initiation and progression. The recent development of small-molecule kinase inhibitors for the treatment of diverse types of cancer has proven successful in clinical therapy. Kinase inhibitors represent targeted therapy resulting from the understanding of molecular genetics and molecular signaling pathways. This class of therapeutics represents a transformation from conventional chemotherapy to targeted cancer treatment. Nevertheless, many factors confound the clinical efficacy of these molecules. Specific tumor genetics, tumor microenvironment, drug resistance, and pharmacogenomics determine how useful a compound will be in the treatment of a given cancer. Due to the clinical importance of kinase inhibitors, multiple strategies are required to overcome resistance mechanisms and develop more effective targeted therapies. Moreover, kinase inhibitors are not only important for the treatment of cancer but also help us better understand the physiological roles of kinases. This Special Issue intends to serve as a compilation overviewing kinase signaling and kinase-targeted drug discovery and development in relation to oncology and highlighting the challenges and future potential for kinase-targeted cancer therapies.

Prof. Dr. Valentina De Falco
Guest Editor

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Keywords

  • cancer
  • oncogene
  • kinase inhibitors
  • tumor drug resistance
  • signal transduction
  • survival
  • cell reprogramming
  • target therapy
  • cancer heterogeneity
  • biomarkers

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Related Special Issue

Published Papers (3 papers)

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Research

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21 pages, 12450 KiB  
Article
The Alternative TrkAIII Splice Variant, a Targetable Oncogenic Participant in Human Cutaneous Malignant Melanoma
by Lucia Cappabianca, Veronica Zelli, Cristina Pellegrini, Michela Sebastiano, Rita Maccarone, Marco Clementi, Alessandro Chiominto, Pierdomenico Ruggeri, Ludovica Cardelli, Marianna Ruggieri, Maddalena Sbaffone, Maria-Concetta Fargnoli, Stefano Guadagni, Antonietta R. Farina and Andrew R. Mackay
Cells 2023, 12(2), 237; https://doi.org/10.3390/cells12020237 - 5 Jan 2023
Cited by 1 | Viewed by 1950
Abstract
Post-therapeutic relapse, poor survival rates and increasing incidence justify the search for novel therapeutic targets and strategies in cutaneous malignant melanoma (CMM). Within this context, a potential oncogenic role for TrkA in CMM is suggested by reports of NTRK1 amplification, enhanced TrkA expression [...] Read more.
Post-therapeutic relapse, poor survival rates and increasing incidence justify the search for novel therapeutic targets and strategies in cutaneous malignant melanoma (CMM). Within this context, a potential oncogenic role for TrkA in CMM is suggested by reports of NTRK1 amplification, enhanced TrkA expression and intracellular TrkA activation associated with poor prognosis. TrkA, however, exhibits tumour-suppressing properties in melanoma cell lines and has recently been reported not to be associated with CMM progression. To better understand these contradictions, we present the first analysis of potential oncogenic alternative TrkA mRNA splicing, associated with TrkA immunoreactivity, in CMMs, and compare the behaviour of fully spliced TrkA and the alternative TrkAIII splice variant in BRAF(V600E)-mutated A375 melanoma cells. Alternative TrkA splicing in CMMs was associated with unfolded protein response (UPR) activation. Of the several alternative TrkA mRNA splice variants detected, TrkAIII was the only variant with an open reading frame and, therefore, oncogenic potential. TrkAIII expression was more frequent in metastatic CMMs, predominated over fully spliced TrkA mRNA expression in ≈50% and was invariably linked to intracellular phosphorylated TrkA immunoreactivity. Phosphorylated TrkA species resembling TrkAIII were also detected in metastatic CMM extracts. In A375 cells, reductive stress induced UPR activation and promoted TrkAIII expression and, in transient transfectants, promoted TrkAIII and Akt phosphorylation, enhancing resistance to reductive stress-induced death, which was prevented by lestaurtinib and entrectinib. In contrast, fully spliced TrkA was dysfunctional in A375 cells. The data identify fully spliced TrkA dysfunction as a novel mechanism for reducing melanoma suppression, support a causal relationship between reductive stress, UPR activation, alternative TrkAIII splicing and TrkAIII activation and characterise a targetable oncogenic pro-survival role for TrkAIII in CMM. Full article
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24 pages, 11626 KiB  
Article
The Influence of PARP, ATR, CHK1 Inhibitors on Premature Mitotic Entry and Genomic Instability in High-Grade Serous BRCAMUT and BRCAWT Ovarian Cancer Cells
by Patrycja Gralewska, Arkadiusz Gajek, Dorota Rybaczek, Agnieszka Marczak and Aneta Rogalska
Cells 2022, 11(12), 1889; https://doi.org/10.3390/cells11121889 - 10 Jun 2022
Cited by 6 | Viewed by 2908
Abstract
Olaparib is a poly (ADP-ribose) polymerase inhibitor (PARPi) that inhibits PARP1/2, leading to replication-induced DNA damage that requires homologous recombination repair. Olaparib is often insufficient to treat BRCA-mutated (BRCAMUT) and BRCA wild-type (BRCAWT) high-grade serous ovarian [...] Read more.
Olaparib is a poly (ADP-ribose) polymerase inhibitor (PARPi) that inhibits PARP1/2, leading to replication-induced DNA damage that requires homologous recombination repair. Olaparib is often insufficient to treat BRCA-mutated (BRCAMUT) and BRCA wild-type (BRCAWT) high-grade serous ovarian carcinomas (HGSOCs). We examined the short-term (up to 48 h) efficacy of PARPi treatment on a DNA damage response pathway mediated by ATR and CHK1 kinases in BRCAMUT (PEO-1) and BRCAWT (SKOV-3 and OV-90) cells. The combination of ATRi/CHK1i with PARPi was not more cytotoxic than ATR and CHK1 monotherapy. The combination of olaparib with inhibitors of the ATR/CHK1 pathway generated chromosomal abnormalities, independent on BRCAMUT status of cells and formed of micronuclei (MN). However, the beneficial effect of the PARPi:ATRi combination on MN was seen only in the PEO1 BRCAMUT line. Monotherapy with ATR/CHK1 inhibitors reduced BrdU incorporation due to a slower rate of DNA synthesis, which resulted from elevated levels of replication stress, while simultaneous blockade of PARP and ATR caused beneficial effects only in OV-90 cells. Inhibition of ATR/CHK1 increased the formation of double-strand breaks as measured by increased γH2AX expression at collapsed replication forks, resulting in increased levels of apoptosis. Our findings indicate that ATR and CHK1 inhibitors provoke premature mitotic entry, leading to genomic instability and ultimately cell death. Full article
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Review

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22 pages, 1872 KiB  
Review
Ibrutinib in the Treatment of Solid Tumors: Current State of Knowledge and Future Directions
by Katarzyna Szklener, Adam Michalski, Klaudia Żak, Michał Piwoński and Sławomir Mańdziuk
Cells 2022, 11(8), 1338; https://doi.org/10.3390/cells11081338 - 14 Apr 2022
Cited by 19 | Viewed by 4950
Abstract
Bruton’s Tyrosine Kinase (BTK) is considered crucial in the activation and survival of both physiological and malignant B-cells. In recent years, ibrutinib, an oral BTK inhibitor, became a breakthrough therapy for hematological malignancies, such as chronic lymphocytic. However, ibrutinib’s feasibility might not end [...] Read more.
Bruton’s Tyrosine Kinase (BTK) is considered crucial in the activation and survival of both physiological and malignant B-cells. In recent years, ibrutinib, an oral BTK inhibitor, became a breakthrough therapy for hematological malignancies, such as chronic lymphocytic. However, ibrutinib’s feasibility might not end there. Several other kinases with established involvement with solid malignancies (i.e., EGFR, HER2) have been found to be inhibited by this agent. Recent discoveries indicate that BTK is a potential anti-solid tumor therapy target. Consequently, ibrutinib, a BTK-inhibitor, has been studied as a therapeutic option in solid malignancies. While most preclinical studies indicate ibrutinib to be an effective therapeutic option in some specific indications, such as NSCLC and breast cancer, clinical trials contradict these observations. Nevertheless, while ibrutinib failed as a monotherapy, it might become an interesting part of a multidrug regime: not only has a synergism between ibrutinib and other compounds, such as trametinib or dactolisib, been observed in vitro, but this BTK inhibitor has also been established as a radio- and chemosensitizer. This review aims to describe the milestones in translating BTK inhibitors to solid tumors in order to understand the future potential of this agent better. Full article
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