Non-small cell lung cancer (NSCLC) is largely promoted by a multistep tumorigenesis process involving various genetic and epigenetic alterations, which essentially contribute to the high incidence of mortality among patients with NSCLC. Clinical observations revealed that NSCLC also co-opts a multifaceted immune checkpoint dysregulation as an important driving factor in NSCLC progression and development. For example, a deregulated PI3K/AKT/mTOR pathway has been noticed in 50-70% of NSCLC cases, primarily modulated by mutations in key oncogenes such as ALK, EGFR, KRAS, and others. Additionally, genetic association studies containing patient-specific factors and local reimbursement criteria expose/reveal mutations in EGFR/ALK/ROS/BRAF/KRAS/PD-L1 proteins to determine the suitability of available immunotherapy or tyrosine kinase inhibitor therapy. Thus, the expression of such checkpoints on tumors and immune cells is pivotal in understanding the therapeutic efficacy and has been extensively studied for NSCLC treatments. Therefore, this review summarizes current knowledge in NSCLC tumorigenesis, focusing on its genetic and epigenetic intricacies, immune checkpoint dysregulation, and the evolving landscape of targeted therapies. In the context of current and future therapies, we emphasize the significance of antibodies targeting PD-1/PD-L1 and CTLA-4 interactions as the primary therapeutic strategy for immune system reactivation in NSCLC. Other approaches involving the promising potential of nanobodies, probodies, affibodies, and DARPINs targeting immune checkpoints are also described; these are under active research or clinical trials to mediate immune regulation and reduce cancer progression. This comprehensive review underscores the multifaceted nature, current state and future directions of NSCLC research and treatment.

• MeSH
• antigeny CD274 metabolismus   MeSH
• erbB receptory metabolismus   MeSH
• fosfatidylinositol-3-kinasy metabolismus   MeSH
• karcinogeneze MeSH
• lidé MeSH
• nádorová transformace buněk MeSH
• nádory plic * farmakoterapie   genetika   MeSH
• nemalobuněčný karcinom plic * farmakoterapie   genetika   MeSH
• protoonkogenní proteiny p21(ras) MeSH
• tyrosinkinasové receptory metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Sphingomyelinase D (SMase D), the main toxic component of Loxosceles venom, has a well-documented role on dermonecrotic lesion triggered by envenomation with these species; however, the intracellular mechanisms involved in this event are still poorly known. Through differential transcriptomics of human keratinocytes treated with L. laeta or L. intermedia SMases D, we identified 323 DEGs, common to both treatments, as well as upregulation of molecules involved in the IL-1 and ErbB signaling. Since these pathways are related to inflammation and wound healing, respectively, we investigated the relative expression of some molecules related to these pathways by RT-qPCR and observed different expression profiles over time. Although, after 24 h of treatment, both SMases D induced similar modulation of these pathways in keratinocytes, L. intermedia SMase D induced earlier modulation compared to L. laeta SMase D treatment. Positive expression correlations of the molecules involved in the IL-1 signaling were also observed after SMases D treatment, confirming their inflammatory action. In addition, we detected higher relative expression of the inhibitor of the ErbB signaling pathway, ERRFI1, and positive correlations between this molecule and pro-inflammatory mediators after SMases D treatment. Thus, herein, we describe the cell pathways related to the exacerbation of inflammation and to the failure of the wound healing, highlighting the contribution of the IL-1 signaling pathway and the ERRFI1 for the development of cutaneous loxoscelism.

• MeSH
• erbB receptory metabolismus   MeSH
• fosfodiesterasy toxicita   MeSH
• interleukin-1 metabolismus   MeSH
• kousnutí pavoukem patologie   MeSH
• lidé MeSH
• pavoučí jedy * toxicita   MeSH
• pavouci chemie   metabolismus   MeSH
• sfingomyelinfosfodiesterasa * metabolismus   MeSH
• signální transdukce MeSH
• zánět MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The cytokine interleukin-6 (IL-6) has considerable pro-inflammatory properties and is a driver of many physiological and pathophysiological processes. Cellular responses to IL-6 are mediated by membrane-bound or soluble forms of the IL-6 receptor (IL-6R) complexed with the signal-transducing subunit gp130. While expression of the membrane-bound IL-6R is restricted to selected cell types, soluble IL-6R (sIL-6R) enables gp130 engagement on all cells, a process termed IL-6 trans-signalling and considered to be pro-inflammatory. sIL-6R is predominantly generated through proteolytic processing by the metalloproteinase ADAM17. ADAM17 also liberates ligands of the epidermal growth factor receptor (EGFR), which is a prerequisite for EGFR activation and results in stimulation of proliferative signals. Hyperactivation of EGFR mostly due to activating mutations drives cancer development. Here, we reveal an important link between overshooting EGFR signalling and the IL-6 trans-signalling pathway. In epithelial cells, EGFR activity induces not only IL-6 expression but also the proteolytic release of sIL-6R from the cell membrane by increasing ADAM17 surface activity. We find that this derives from the transcriptional upregulation of iRhom2, a crucial regulator of ADAM17 trafficking and activation, upon EGFR engagement, which results in increased surface localization of ADAM17. Also, phosphorylation of the EGFR-downstream mediator ERK mediates ADAM17 activity via interaction with iRhom2. In sum, our study reveals an unforeseen interplay between EGFR activation and IL-6 trans-signalling, which has been shown to be fundamental in inflammation and cancer.

• MeSH
• cytokinový receptor gp130 genetika   MeSH
• epitelové buňky metabolismus   MeSH
• erbB receptory genetika   metabolismus   MeSH
• interleukin-6 * genetika   metabolismus   MeSH
• lidé MeSH
• protein ADAM17 * MeSH
• signální transdukce * genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The epidermal growth factor (EGF) and its receptor (EGFR) gene-gene interactions were shown to increase the susceptibility to esophageal cancer. However, the role of the EGF/EGFR pathway in the development of gastroesophageal reflux disease (GERD) and its complications (reflux esophagitis (RE), Barrett's esophagus (BE), and esophageal adenocarcinoma (EAC)) remains unclear. This association study is aimed at investigating functional EGF and EGFR gene polymorphisms, their mRNA expression in esophageal tissues, and EGF plasma levels in relation to RE, BE, and EAC development in the Central European population. 301 patients with RE/BE/EAC (cases) as well as 98 patients with nonerosive reflux disease (NERD) and 8 healthy individuals (controls) were genotyped for +61 A>G EGF (rs4444903) and +142285 G>A EGFR (rs2227983) polymorphisms using the TaqMan quantitative polymerase chain reaction (qPCR). In random subgroups, the EGF and EGFR mRNA expressions were analyzed by reverse transcription qPCR in esophageal tissue with and without endoscopically visible pathological changes; and the EGF plasma levels were determined by enzyme-linked immunosorbent assay. None of the genotyped SNPs nor EGF-EGFR genotype interactions were associated with RE, BE, or EAC development (p > 0.05). Moreover, mRNA expression of neither EGF nor EGFR differed between samples of the esophageal tissue with and without endoscopically visible pathology (p > 0.05) nor between samples from patients with different diagnoses, i.e., RE, BE, or EAC (p > 0.05). Nevertheless, the lower EGF mRNA expression in carriers of combined genotypes AA +61 EGF (rs4444903) and GG +142285 EGFR (rs2227983; p < 0.05) suggests a possible direct/indirect effect of EGF-EGFR gene interactions on EGF gene expression. In conclusion, EGF and EGFR gene variants and their mRNA/protein expression were not associated with RE, BE or EAC development in the Central European population.

• MeSH
• adenokarcinom * patologie   MeSH
• Barrettův syndrom * metabolismus   MeSH
• epidermální růstový faktor genetika   MeSH
• erbB receptory genetika   metabolismus   MeSH
• gastroezofageální reflux * genetika   MeSH
• jednonukleotidový polymorfismus MeSH
• lidé MeSH
• messenger RNA MeSH
• nádory jícnu * patologie   MeSH
• peptická ezofagitida * genetika   MeSH
• studie případů a kontrol MeSH
• transportní proteiny genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Despite constant advances in the field of pediatric oncology, the survival rate of high-risk neuroblastoma patients remains poor. The molecular and genetic features of neuroblastoma, such as MYCN amplification and stemness status, have established themselves not only as potent prognostic and predictive factors but also as intriguing targets for personalized therapy. Novel thiosemicarbazones target both total level and activity of a number of proteins involved in some of the most important signaling pathways in neuroblastoma. In this study, we found that di-2-pyridylketone 4-cyclohexyl-4-methyl-3-thiosemicarbazone (DpC) potently decreases N-MYC in MYCN-amplified and c-MYC in MYCN-nonamplified neuroblastoma cell lines. Furthermore, DpC succeeded in downregulating total EGFR and phosphorylation of its most prominent tyrosine residues through the involvement of NDRG1, a positive prognostic marker in neuroblastoma, which was markedly upregulated after thiosemicarbazone treatment. These findings could provide useful knowledge for the treatment of MYC-driven neuroblastomas that are unresponsive to conventional therapies.

• MeSH
• amplifikace genu účinky léků   MeSH
• biologické modely MeSH
• chelátory železa farmakologie   MeSH
• down regulace účinky léků   MeSH
• erbB receptory metabolismus   MeSH
• fosforylace účinky léků   MeSH
• fyziologický stres účinky léků   MeSH
• intracelulární signální peptidy a proteiny metabolismus   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• neuroblastom metabolismus   patologie   MeSH
• proteiny buněčného cyklu metabolismus   MeSH
• protoonkogen n-myc metabolismus   MeSH
• protoonkogenní proteiny c-akt metabolismus   MeSH
• pyridiny farmakologie   MeSH
• signální transdukce * MeSH
• thiosemikarbazony farmakologie   MeSH
• tvar buňky účinky léků   MeSH
• umlčování genů účinky léků   MeSH
• upregulace účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

OBJECTIVES: Patients with head and neck squamous cell carcinoma (HNSCC) can experience severe symptom burden and/or difficulty swallowing, leading to problems with treatment adherence/administration. In LUX-Head and Neck 1 (LH&N1; NCT01345682), second-line afatinib improved progression-free survival (PFS) versus methotrexate in patients with recurrent/metastatic HNSCC. We report adherence and safety across pre-specified and additional subgroups potentially linked to afatinib PFS benefit in LH&N1 (p16 status, smoking history), and afatinib adherence, safety and efficacy by administration (oral versus feeding tube; post-hoc analysis). METHODS: Patients were randomized (2:1) to afatinib (40 mg/day) or intravenous methotrexate (40 mg/m2/week). RESULTS: Among 320 afatinib-treated and 160 methotrexate-treated patients, 83-92% and 76-92% (of patients with data available) across all subgroups took ≥80% of treatment. Across p16 status and smoking history subgroups, the most common treatment-related adverse events (AEs) were diarrhea (70-91%), rash/acne (72-84%), stomatitis (34-73%) with afatinib; and included stomatitis (39-100%), fatigue (22-50%), nausea (19-36%) with methotrexate. Dose reduction decreased AE incidence/severity. Baseline characteristics were generally similar between oral/feeding tube (n = 276/n = 46) groups. 89%/89% (of patients with data available) took ≥80% of assigned afatinib. Median PFS was 2.6 versus 2.7 months (hazard ratio: 0.997; 95% confidence interval: 0.72-1.38). The most common afatinib-related AEs were: rash/acne (74% versus 74%), diarrhea (73% versus 65%), stomatitis (40% versus 30%). CONCLUSION: Subgroup analyses of LH&N1 demonstrate that afatinib has predictable and manageable safety across patient subgroups, with high treatment adherence, and is effective via oral and feeding tube administration.

• MeSH
• adherence a compliance při léčbě MeSH
• afatinib terapeutické užití   MeSH
• chinazoliny aplikace a dávkování   MeSH
• dlaždicobuněčné karcinomy hlavy a krku farmakoterapie   metabolismus   MeSH
• erbB receptory metabolismus   MeSH
• lidé MeSH
• lokální recidiva nádoru farmakoterapie   metabolismus   MeSH
• methotrexát aplikace a dávkování   MeSH
• nádory hlavy a krku farmakoterapie   metabolismus   MeSH
• přežití bez známek nemoci MeSH
• protokoly protinádorové kombinované chemoterapie terapeutické užití   MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH

The maturation of mammalian oocytes in vitro can be stimulated by gonadotropins (follicle-stimulating hormone, FSH) or their intrafollicular mediator, epidermal growth factor (EGF)-like peptide-amphiregulin (AREG). We have shown previously that in pig cumulus-oocyte complexes (COCs), FSH induces expression and the synthesis of AREG that binds to EGF receptor (EGFR) and activates the mitogen-activated protein kinase 3/1 (MAPK3/1) signaling pathway. However, in this study we found that FSH also caused a rapid activation of MAPK3/1 in the cumulus cells, which cannot be explained by the de novo synthesis of AREG. The rapid MAPK3/1 activation required EGFR tyrosine kinase (TK) activity, was sensitive to SRC proto-oncogene non-receptor tyrosine kinase (SRC)-family and protein kinase C (PKC) inhibitors, and was resistant to inhibitors of protein kinase A (PKA) and metalloproteinases. AREG also induced the rapid activation of MAPK3/1 in cumulus cells, but this activation was only dependent on the EGFR TK activity. We conclude that in cumulus cells, FSH induces a rapid activation of MAPK3/1 by the ligand-independent transactivation of EGFR, requiring SRC and PKC activities. This rapid activation of MAPK3/1 precedes the second mechanism participating in the generation and maintenance of active MAPK3/1-the ligand-dependent activation of EGFR depending on the synthesis of EGF-like peptides.

• MeSH
• aktivace transkripce MeSH
• amfiregulin metabolismus   MeSH
• erbB receptory metabolismus   MeSH
• extracelulárním signálem regulované MAP kinasy genetika   MeSH
• folikuly stimulující hormon farmakologie   MeSH
• IVM techniky MeSH
• kultivované buňky MeSH
• kumulární buňky cytologie   účinky léků   metabolismus   MeSH
• mitogenem aktivovaná proteinkinasa 1 genetika   MeSH
• mitogenem aktivovaná proteinkinasa 3 genetika   MeSH
• oocyty cytologie   účinky léků   metabolismus   MeSH
• prasata MeSH
• signální transdukce účinky léků   MeSH
• skupina kinas odvozených od src-genu metabolismus   MeSH
• zvířata MeSH
• Check Tag
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The transient receptor potential vanilloid 3 (TRPV3) channel is a Ca2+-permeable thermosensitive ion channel widely expressed in keratinocytes, where together with epidermal growth factor receptor (EGFR) forms a signaling complex regulating epidermal homeostasis. Proper signaling through this complex is achieved and maintained via several pathways in which TRPV3 activation is absolutely required. Results of recent studies have suggested that low-level constitutive activity of TRPV3 induces EGFR-dependent signaling that, in turn, amplifies TRPV3 via activation of the mitogen-activated protein kinase ERK in a positive feedback loop. Here, we explored the molecular mechanism that increases TRPV3 activity through EGFR activation. We used mutagenesis and whole-cell patch clamp experiments on TRPV3 channels endogenously expressed in an immortalized human keratinocyte cell line (HaCaT) and in transiently transfected HEK293T cells and found that the sensitizing effect of EGFR on TRPV3 is mediated by ERK. We observed that ERK-mediated phosphorylation of TRPV3 alters its responsiveness to repeated chemical stimuli. Among several putative ERK phosphorylation sites, we identified threonine 264 in the N-terminal ankyrin repeat domain as the most critical site for the ERK-dependent modulation of TRPV3 channel activity. Of note, Thr264 is in close vicinity to a structurally and functionally important TRPV3 region comprising an atypical finger 3 and oxygen-dependent hydroxylation site. In summary, our findings indicate that Thr264 in TRPV3 is a key ERK phosphorylation site mediating EGFR-induced sensitization of the channel to stimulate signaling pathways involved in regulating skin homeostasis.

• MeSH
• epidermální růstový faktor metabolismus   MeSH
• erbB receptory agonisté   metabolismus   MeSH
• fosforylace účinky léků   MeSH
• HEK293 buňky MeSH
• interakční proteinové domény a motivy MeSH
• kationtové kanály TRPV agonisté   chemie   genetika   metabolismus   MeSH
• keratinocyty účinky léků   enzymologie   metabolismus   MeSH
• lidé MeSH
• MAP kinasový signální systém * účinky léků   MeSH
• metoda terčíkového zámku MeSH
• mitogenem aktivovaná proteinkinasa 3 chemie   genetika   metabolismus   MeSH
• modulátory membránového transportu farmakologie   MeSH
• monoterpeny farmakologie   MeSH
• mutace MeSH
• mutageneze cílená MeSH
• posttranslační úpravy proteinů účinky léků   MeSH
• rekombinantní proteiny chemie   metabolismus   MeSH
• sloučeniny boru farmakologie   MeSH
• threonin metabolismus   MeSH
• transformované buněčné linie MeSH
• upregulace * účinky léků   MeSH
• zelené fluorescenční proteiny genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The surge in luteinizing hormone (LH) in preovulatory ovarian follicles triggers the resumption of oocyte meiosis accompanied by expansion of surrounding cumulus cells and ovulation of cumulus-oocyte complexes (COCs) into the oviduct. Over the last 15 years, substantial progress has been made in elucidating the key pathways by which the LH signal spreads within the preovulatory follicle and in identifying the molecules responsible for maintaining oocyte arrest and meiosis resumption. It is now clear that the adenylcyclase-mediated rise in intracellular cyclic adenosine monophosphate leads to activation of the epidermal growth factor receptor (EGFR) network in granulosa and cumulus cells. This signaling network can control the transcription of key genes required for cell metabolism, cumulus expansion, and oocyte meiosis resumption. In addition, EGFR signaling is involved in the regulation of gap junctional communication within follicular somatic cells, and in this way it can control the diffusion of meiosis-arresting molecules as well as energy substrates into the oocyte. Thus, the proper functioning of the follicular EGFR network is a vital precondition for the production of matured and developmentally competent oocytes. However, most current in vitro maturation systems are based on a culture of COCs isolated from growing follicles, in which function of the EGFR network may be insufficient for promoting oocyte meiotic and developmental competence. This review focuses on research identifying the importance of the EGFR signaling in somatic follicular cells for oocyte meiotic and developmental competence, and on special approaches to the culture of COCs isolated from growing follicles to promote oocyte quality.

• MeSH
• erbB receptory genetika   metabolismus   MeSH
• meióza fyziologie   MeSH
• oocyty fyziologie   MeSH
• savci fyziologie   MeSH
• signální transdukce fyziologie   MeSH
• zvířata MeSH
• Check Tag
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Mezi inhibitory receptoru pro epidermální růstový faktor (epidermal growth factor receptor, EGFR) používané při terapii pacientů s pokročilým nemalobuněčným karcinomem plic patří v České republice registrované gefitinib, erlotinib, afatinib a osimertinib. Tato léčiva mohou vyvolávat řadu lékových interakcí různého klinického významu. Rozsah a závažnost lékových interakcí jsou dány vlastnostmi jednotlivých léčiv z hlediska jejich biotransformace, transportu a rozpustnosti ve vodě při pH vyšším než 6. S pomocí údajů obsažených v Databázi lékových interakcí DrugAgency a dalších informací publikovaných v odborné literatuře v letech 2002–2017 bylo prokázáno, že nejvyšší interakční potenciál, tj. schopnost vyvolávat klinicky významné lékové interakce, má erlotinib, mírně menší interakční potenciál pak gefitinib a významně nižší interakční potenciál má osimertinib a zejména afatinib. Ten také lze z hlediska lékových interakcí považovat za nejbezpečnější inhibitor EGFR.

Inhibitors of epidermal growth factor receptor used in the therapy of patients with advanced non‑small‑cell lung carcinoma include gefitinib, erlotinib, afatinib and osimertinib approved in the Czech Republic. These drugs can cause a range of drug interactions of variable clinical significance. The extent and severity of drug interactions are defined by characteristics of the individual drugs, regarding their biotransformation, transport and solubility in water while pH is higher than 6. Based on the data in the drug interaction database DrugAgency and further information published in medical literature in 2002–2017, it has been confirmed that the highest interaction potential, i.e., the ability to cause clinically relevant drug interactions, is associated with erlotinib and gefitinib has slightly lower interaction potential whereas osimertinib and particularly afatinib show significantly lower interaction potential. With respect to drug interactions, afatinib can be considered as the safest EGFR inhibitor.

• MeSH
• erbB receptory antagonisté a inhibitory   genetika   metabolismus   MeSH
• erlotinib farmakologie   metabolismus   terapeutické užití   MeSH
• hodnocení rizik MeSH
• induktory cytochromu P450 MeSH
• inhibitory cytochromu P450 MeSH
• inhibitory proteinkinas * farmakologie   metabolismus   škodlivé účinky   MeSH
• inhibitory protonové pumpy farmakokinetika   farmakologie   terapeutické užití   MeSH
• lékové interakce MeSH
• lidé MeSH
• metabolické vedlejší účinky léčivých látek MeSH
• statiny farmakokinetika   farmakologie   terapeutické užití   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH