RESUMEN
HER2 activating mutations have emerged as oncogenic drivers and therapeutic targets in a variety of human tumors. In breast cancer, these deregulations occur at low frequency, and are mostly detected in HER2-nonamplified, metastatic disease. Preclinical evidence has clarified the role of hotspot mutations in HER2 constitutive activation, defining them as an alternative mechanism to HER2 gene amplification. Furthermore, recent clinical studies have indicated the emergence of newly acquired HER2 deregulations in significant proportions of breast cancer patients who experience disease progression following both endocrine and HER2-targeted therapies. As the involvement of HER2 mutation in therapy resistance may profoundly impact patient outcomes on successive therapies, several clinical trials are currently investigating the efficacy of various HER2-targeted drugs in HER2-mutant breast cancer. In this review, we firstly summarize the structural organization of the HER2 oncogene and its historical impact on breast cancer prognosis and therapeutic advancement. Then, we provide an overview of the frequencies and functional relevance of clinically recurrent HER2 mutations in breast cancer with a special focus on their role in therapeutic resistance. Finally, we provide a collection of the clinical trials that are currently exploring novel therapeutic approaches for this patient subset and discuss the related perspectives and challenges.
Asunto(s)
Neoplasias de la Mama , Resistencia a Antineoplásicos , Mutación , Receptor ErbB-2 , Humanos , Neoplasias de la Mama/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Receptor ErbB-2/genética , Femenino , Resistencia a Antineoplásicos/genética , Terapia Molecular Dirigida/métodos , Pronóstico , Ensayos Clínicos como Asunto , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacologíaRESUMEN
BACKGROUND: First identified in Drosophila melanogaster, the Hippo pathway is considered a major regulatory cascade controlling tissue homeostasis and organ development. Hippo signaling components include kinases whose activity regulates YAP and TAZ final effectors. In response to upstream stimuli, YAP and TAZ control transcriptional programs involved in cell proliferation, cytoskeletal reorganization and stemness. MAIN TEXT: While fine tuning of Hippo cascade components is essential for maintaining the balance between proliferative and non-proliferative signals, pathway signaling is frequently dysregulated in gastrointestinal cancers. Also, YAP/TAZ aberrant activation has been described in conditions characterized by chronic inflammation that precede cancer development, suggesting a role of Hippo effectors in triggering carcinogenesis. In this review, we summarize the architecture of the Hippo pathway and discuss the involvement of signaling cascade unbalances in premalignant lesions of the gastrointestinal tract, providing a focus on the underlying molecular mechanisms. CONCLUSIONS: The biology of premalignant Hippo signaling dysregulation needs further investigation in order to elucidate the evolutionary trajectories triggering cancer inititation and develop effective early therapeutic strategies targeting the Hippo/YAP pathway.
Asunto(s)
Vía de Señalización Hippo , Neoplasias , Animales , Drosophila melanogaster , Neoplasias/tratamiento farmacológico , Transducción de Señal , Tracto GastrointestinalRESUMEN
Human DNA topoisomerase IB controls the topological state of supercoiled DNA through a complex catalytic cycle that consists of cleavage and religation reactions, allowing the progression of fundamental DNA metabolism. The catalytic steps of human DNA topoisomerase IB were analyzed in the presence of a drug, obtained by the open-access drug bank Medicines for Malaria Venture. The experiments indicate that the compound strongly and irreversibly inhibits the cleavage step of the enzyme reaction and reduces the cell viability of three different cancer cell lines. Molecular docking and molecular dynamics simulations suggest that the drug binds to the human DNA topoisomerase IB-DNA complex sitting inside the catalytic site of the enzyme, providing a molecular explanation for the cleavage-inhibition effect. For all these reasons, the aforementioned drug could be a possible lead compound for the development of an efficient anti-tumor molecule targeting human DNA topoisomerase IB.
Asunto(s)
Antimaláricos/farmacología , Antineoplásicos/farmacología , Simulación por Computador , ADN-Topoisomerasas de Tipo I/química , ADN/metabolismo , Inhibidores de Topoisomerasa I/farmacología , Catálisis , Dominio Catalítico , ADN/química , ADN/efectos de los fármacos , ADN-Topoisomerasas de Tipo I/metabolismo , Humanos , Técnicas In Vitro , Simulación del Acoplamiento Molecular , Simulación de Dinámica Molecular , Conformación de Ácido Nucleico , Conformación ProteicaRESUMEN
DNA topoisomerases are key enzyme responsible for modulating the topological state of the DNA by breaking and rejoining of DNA strand. Characterization of a Gly717Asp mutation in the human topoisomerase was performed using several catalytic assays. The mutant enzyme was shown to have comparable cleavage and fast religation rate as compared to the wild-type protein. Addition of the anticancer drug camptothecin significantly reduced the religation step. The simulative approaches and analysis of the cleavage/religation equilibrium indicate that the mutation is able to modify the architecture of the drug binding site, increasing the persistence of the drug for the enzyme-DNA covalent complex. Taken together these results indicate that the structure modification of the drug binding site is the key reason for the increasing CPT persistence and furthermore provide the possibility for new anti-cancer drug discovery.
Asunto(s)
Antineoplásicos Fitogénicos/farmacología , Ácido Aspártico/química , Camptotecina/farmacología , ADN-Topoisomerasas de Tipo I/metabolismo , Glicina/química , Mutación , Antineoplásicos Fitogénicos/metabolismo , Sitios de Unión , Camptotecina/metabolismo , ADN-Topoisomerasas de Tipo I/química , ADN-Topoisomerasas de Tipo I/genética , Resistencia a Antineoplásicos/genética , Humanos , Cinética , ProteolisisRESUMEN
The Hippo pathway plays a critical role for balancing proliferation and differentiation, thus regulating tissue homeostasis. The pathway acts through a kinase cascade whose final effectors are the Yes-associated protein (YAP) and its paralog transcriptional coactivator with PDZbinding motif (TAZ). In response to a variety of upstream signals, YAP and TAZ activate a transcriptional program that modulates cellular proliferation, tissue repair after injury, stem cell fate decision, and cytoskeletal reorganization. Hippo pathway signaling is often dysregulated in gastric cancer and in Helicobacter pylori-induced infection, suggesting a putative role of its deregulation since the early stages of the disease. In this review, we summarize the architecture and regulation of the Hippo pathway and discuss how its dysregulation fuels the onset and progression of gastric cancer. In this setting, we also focus on the crosstalk between Hippo and other established oncogenic signaling pathways. Lastly, we provide insights into the therapeutic approaches targeting aberrant YAP/TAZ activation and discuss the related clinical perspectives and challenges.
Asunto(s)
Infecciones por Helicobacter , Vía de Señalización Hippo , Neoplasias Gástricas , Humanos , Transformación Celular Neoplásica , Infecciones por Helicobacter/genética , Helicobacter pylori , Proteínas Serina-Treonina Quinasas/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/microbiología , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Homotaurine is a potential therapeutic compound for treatment of Alzheimer's disease (AD), but its efficacy is still under investigation. Emerging data have shown that other than neuroprotective, homotaurine is endowed with anti-inflammatory activities, though with still unclear underlying mechanisms. Inflammation plays a critical role in the pathogenesis of AD and we previously suggested that homotaurine supplementation in patients with amnestic mild cognitive impairment (MCI) plays beneficial effects associated to a decrease in the circulating levels of the pro-inflammatory cytokine IL-18. Here we report that MCI patients supplemented with homotaurine for 12 months show elevated serum levels of IL-10 and IL-33, as compared to baseline, in addition to the described IL-18 decrease. Furthermore, we observed a significant positive correlation between IL-10 and IL-33 levels after treatment but not at the baseline, underlining the effectiveness of the compound in modulating both cytokines in an inter-related fashion and in regulating the pro/anti-inflammation balance. Furthermore, the elevation of both IL-10 and IL-33 is significantly associated with an improvement of episodic memory of treated patients, as measured by the Delayed Verbal Ray Test. In conclusion, our results confirm that homotaurine treatment exerts an overall anti-inflammatory action in MCI patients, based not only on the down-regulation of pro-inflammatory IL-18, but also on up-regulation of the anti-inflammatory IL-33 and IL-10 cytokines, which in turn are associated with an amelioration of patient's cognitive functions. Future studies should be addressed to investigate the molecular mechanisms of homotaurine anti-inflammatory activity and its therapeutic exploitation in early AD.
Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Enfermedad de Alzheimer/patología , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/patología , Citocinas , Humanos , Interleucina-10 , Interleucina-18 , Interleucina-33 , Taurina/análogos & derivadosRESUMEN
BACKGROUND: DNA topoisomerases 1B are a class of ubiquitous enzyme that solves the topological problems associated with biological processes such as replication, transcription and recombination. Numerous sequence alignment of topoisomerase 1B from different species shows that the lengths of different domains as well as their amino acids sequences are quite different. In the present study a hybrid enzyme, generated by swapping the N-terminal of Plasmodium falciparum into the corresponding domain of the human, has been characterized. METHODS: The chimeric enzyme was generated using different sets of PCR. The in vitro characterization was carried out using different DNA substrate including radio-labelled oligonucleotides. RESULTS: The chimeric enzyme displayed slower relaxation activity, cleavage and re-ligation kinetics strongly perturbed when compared to the human enzyme. CONCLUSION: These results indicate that the N-terminal domain has a crucial role in modulating topoisomerase activity in different species.