RESUMEN
KRAS mutations play a critical role in the development and progression of several cancers, including non-small cell lung cancer and pancreatic cancer. Despite advancements in targeted therapies, the management of KRAS-mutant tumors remains challenging. This study leverages bibliometric analysis and a comprehensive review of clinical trials to identify emerging immunotherapies and potential treatments for KRAS-related cancers. Using the Web of Science Core Collection and Citespace, we analyzed publications from January 2008 to March 2023 alongside 52 clinical trials from ClinicalTrials.gov and WHO's registry, concentrating on immune checkpoint blockades (ICBs) and novel therapies. Our study highlights an increased focus on the tumor immune microenvironment and precision therapy. Clinical trials reveal the effectiveness of ICBs and the promising potential of T-cell receptor T-cell therapy and vaccines in treating KRAS-mutant cancers. ICBs, particularly in combination therapies, stand out in managing KRAS-mutant tumors. Identifying the tumor microenvironment and gene co-mutation profiles as key research areas, our findings advocate for multidisciplinary approaches to advance personalized cancer treatment. Future research should integrate genetic, immunological, and computational studies to unveil new therapeutic targets and refine treatment strategies for KRAS-mutant cancers.
Asunto(s)
Bibliometría , Inmunoterapia , Mutación , Proteínas Proto-Oncogénicas p21(ras) , Humanos , Inmunoterapia/métodos , Proteínas Proto-Oncogénicas p21(ras)/genética , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Ensayos Clínicos como Asunto , Neoplasias/terapia , Neoplasias/genética , Neoplasias/inmunología , Neoplasias/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/terapia , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/inmunologíaRESUMEN
PURPOSE: Non-small cell lung cancer (NSCLC) is a highly fatal malignancy. The Kirsten rat sarcoma viral oncogene (KRAS) gene profoundly impacts patient prognosis. This study aims to explore the correlation between KRAS mutation subtypes, clinical data, and the impact of these subtypes on immunotherapy. MATERIALS AND METHODS: Tumor samples from 269 NSCLC patients at the Affiliated Cancer Hospital of Xinjiang Medical University were analyzed. Patients received first- or second-line therapy without targeted therapy. Molecular and clinical data were used to analysis KRAS mutation subtypes and treatment outcomes. RESULTS: KRAS mutations predominantly included G12C, G12D, and G12V subtypes. TP53 had the highest mutation frequency among KRAS mutations, followed by MST1, STK11, and KMT2C. Gender differences were noted among KRAS mutation subtypes, with G12C and G12V mutations prevalent in males, while G12D mutations were less common among males. Smokers exhibited varied KRAS mutation subtypes, with G12C and G12V prevalent in smokers and G12D in nonsmokers. KRAS mutations were mainly in lung adenocarcinoma. TTF-1 and PD-L1 expression differed significantly among KRAS mutations. Patients with G12C and G12V mutations showed higher TMB levels and better immunotherapy outcomes compared to those without KRAS mutations. Conversely, patients with G12D mutations had poorer immunotherapy responses. CONCLUSIONS: KRAS mutation subtypes exhibit distinct clinical and molecular characteristics and varying responses to immunotherapy. G12C and G12V mutations correlate with better immunotherapy outcomes, while G12D mutations are associated with poorer responses.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Inmunoterapia , Neoplasias Pulmonares , Mutación , Proteínas Proto-Oncogénicas p21(ras) , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/terapia , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Masculino , Proteínas Proto-Oncogénicas p21(ras)/genética , Femenino , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/inmunología , Persona de Mediana Edad , Pronóstico , China/epidemiología , Anciano , Inmunoterapia/métodos , Adulto , Anciano de 80 o más Años , Biomarcadores de Tumor/genéticaRESUMEN
Secondary BRAF variations have been identified as a mechanism of resistance to tyrosine kinase inhibitors (TKIs) in patients with driver gene-positive NSCLC. Nevertheless, there is still a lack of consensus regarding the characteristics and subsequent treatment strategies for these patients. We retrospectively reviewed the medical records of patients with driver gene-positive NSCLC who received TKIs therapy at Zhejiang Cancer Hospital between May 2016 and December 2023. The clinical and genetic characteristics of these patients were assessed, along with the impact of various treatment strategies on survival. This study enrolled 27 patients with advanced NSCLC, in whom BRAF variations occurred at a median time of 28 months after the initiation of targeted therapy. The multivariate accelerated failure time (AFT) model revealed that, compared to chemotherapy-based regimens group, the combined targeted therapy group (p < 0.001) and the combined local treatment group for oligo-progression (p < 0.001) significantly extended patient survival. In contrast, continuing the original signaling pathway's targeted monotherapy was associated with shorter survival (p = 0.034). The median global OS for each treatment group was as follows: chemotherapy-based regimens group, 45 months; combined targeted therapy group, 59 months; combined local treatment group for patients with oligo-progression, 46 months; and targeted monotherapy group, 36 months. Study results indicate that the combination targeted therapy group (including TKIs, BRAF inhibitors, and/or MEK inhibitors) and the localized treatment group are more effective than traditional chemotherapy-based regimens in improving survival. Additionally, continuing targeted monotherapy along the original signaling pathway proves less effective than chemotherapy-based regimens.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Resistencia a Antineoplásicos , Neoplasias Pulmonares , Inhibidores de Proteínas Quinasas , Proteínas Proto-Oncogénicas B-raf , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Femenino , Masculino , Persona de Mediana Edad , Resistencia a Antineoplásicos/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Anciano , Inhibidores de Proteínas Quinasas/uso terapéutico , Estudios Retrospectivos , Terapia Molecular Dirigida/métodos , Adulto , MutaciónRESUMEN
BACKGROUND: Immunotherapy represents a groundbreaking and monumental achievement in the field of cancer therapy, marking a significant advancement in fighting against this devastating disease. Lung cancer has showed consistent clinical improvements in response to immunotherapy treatments, yet, it is undeniable that challenges such as limited response rates acquire resistance, and the unclear fundamental mechanisms were inevitable problems. METHODS: The cellular composition was defined and distinguished through single-cell RNA sequencing (scRNA-seq) analysis of MPR (major pathologic response) and NMPR (non-major pathologic response) samples in GSE207422, including four primary MPR samples and eight primary NMPR samples. RESULTS: We found obvious difference in CD8+ T cell population between MPR and NMPR samples, with high expression of TYMS, RRM2, and BIRC5 in NPMR samples. Meanwhile, the proportion of macrophages and tumor epithelial cells infiltration increased in the NMPR samples. We discovered biomarkers (ACTN4, ATF3, BRD2, CDKN1A, and CHMP4B) in epithelial cells which were potentially represented worse outcomes. CONCLUSIONS: By exploring the difference of tumor microenvironment (TME) in samples with different corresponding degrees of neoadjuvant immunotherapy, this research introduces a number of novel biomarkers for predicting the response of treatment and a theoretical basis for overcoming immunotherapy resistance.
Asunto(s)
Biomarcadores de Tumor , Carcinoma de Pulmón de Células no Pequeñas , Inmunoterapia , Neoplasias Pulmonares , Análisis de la Célula Individual , Microambiente Tumoral , Humanos , Carcinoma de Pulmón de Células no Pequeñas/terapia , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/patología , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Inmunoterapia/métodos , Análisis de la Célula Individual/métodos , Biomarcadores de Tumor/genética , Análisis de Secuencia de ARN/métodos , Regulación Neoplásica de la Expresión Génica , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Perfilación de la Expresión GénicaRESUMEN
Aconiti Lateralis Radix Praeparata (Fuzi in Chinese) is widely used in the clinical treatment of tumors. This study aims to explore the active fractions and underlying mechanisms of Fuzi in the treatment of non-small cell lung cancer (NSCLC). Fuzi alkaloids (FZA) is prepared and found to inhibit the growth of NSCLC both in vitro and in vivo significantly. A total of 53 alkaloids are identified in FZA by UPLC-Q-TOF-MS. Proteomics experiment show that 238 differentially expressed proteins regulated by FZA are involved in amino acid anabolism, pyrimidine metabolism and PI3K/Akt-mTOR signaling pathway. Metabolomics analyses identify 32 significant differential metabolites which are mainly involved in amino acid metabolism, TCA cycle and other pathways. Multi-omics research combined with molecular biological assays suggest that FZA might regulate glycolysis through PI3K/Akt-mTOR pathway to treat NSCLC. The study lays a foundation for the anti-cancer investigation of Fuzi and provides a possible scientific basis for its clinical application.
Asunto(s)
Aconitum , Alcaloides , Carcinoma de Pulmón de Células no Pequeñas , Glucólisis , Neoplasias Pulmonares , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Serina-Treonina Quinasas TOR , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/genética , Serina-Treonina Quinasas TOR/metabolismo , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Humanos , Alcaloides/farmacología , Glucólisis/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacos , Fosfatidilinositol 3-Quinasas/metabolismo , Animales , Aconitum/química , Ratones , Proliferación Celular/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Línea Celular Tumoral , Ratones Desnudos , Antineoplásicos Fitogénicos/farmacología , Ratones Endogámicos BALB C , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Zinc finger MIZ-type containing 2 (ZMIZ2) can function as a coactivator and participate in the progression of certain malignant tumors; however, its expression and underlying molecular mechanism in non-small-cell lung cancer (NSCLC) remains unknown. In this study, we aim to analyze the expression of ZMIZ2 and its tumorigenic function in NSCLC, identifying its related factors. METHODS: ZMIZ2 expression in NSCLC tissue samples and cell lines was examined using immunohistochemistry and western blotting; its biological role was investigated using in vivo and in vitro assays. The association between ZMIZ2 and NAD-dependent protein deacetylase sirtuin-1 (SIRT1) was demonstrated using mass spectrometry and immunoprecipitation experiments. Kyoto Encyclopedia of Genes and Genomes Pathway (KEGG)-based enrichment analysis, luciferase reporter assay, and real-time quantitative polymerase chain reaction (RT-qPCR) were conducted to verify the impact of ZMIZ2-SIRT1 combination on Hippo/Wnt pathways. RESULTS: ZMIZ2 was highly expressed in NSCLC and positively associated with advanced pTNM staging, lymph node metastasis, and poor overall survival. Functional experiments revealed that ZMIZ2 promotes the proliferation, migration, and invasiveness of lung cancer cells-establishing its role as a promoter of oncogenes. Molecular mechanism studies identified SIRT1 as an assisted key factor interacting with ZMIZ2. KEGG enrichment analysis revealed that ZMIZ2 is closely related to Wnt/Hippo pathways; ZMIZ2-SIRT1 interaction enhanced SIRT1 deacetylase activity. Direct downregulation of intranuclear ß-catenin and yes-associated protein (YAP) acetylation levels occurred independently of upstream proteins in Wnt/Hippo pathways; transcriptional activities of ß-catenin-transcription factor 4 (TCF4) and YAP-TEA domain family transcription factors (TEADs) were amplified. CONCLUSIONS: ZMIZ2 promotes the malignant phenotype of lung cancer by regulating Wnt/Hippo pathways through SIRT1, providing an experimental basis for discovering novel biomarkers and developing tumor-targeted drugs.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Vía de Señalización Hippo , Neoplasias Pulmonares , Proteínas Inhibidoras de STAT Activados , Proteínas Serina-Treonina Quinasas , Sirtuina 1 , Vía de Señalización Wnt , Animales , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Células A549 , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Ratones Desnudos , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Sirtuina 1/metabolismo , Sirtuina 1/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Vía de Señalización Wnt/genética , Proteínas Inhibidoras de STAT Activados/genética , Proteínas Inhibidoras de STAT Activados/metabolismoRESUMEN
BACKGROUD: Supernatants from various cytological samples, including body cavity effusion, sputum, bronchoalveolar lavage fluid (BALF), and needle aspiration, have been validated for detecting genetic alterations using cell-free DNA (cfDNA) in patients with non-small cell lung cancer (NSCLC). However, the sensitivity of fusion variations detection remains challenging. The protection of cell-free RNA (cfRNA) is critical for resolving the issue. METHODS: A protective solution (PS) was applied for preserving cfRNA in cytological supernatant (CS), and the quality of protected cfRNA was assessed by cycle threshold (CT) values from reverse transcription quantitative polymerase chain reaction (RT-qPCR). Furthermore, we collected an additional set of malignant cytological and matched tumor samples from 84 NSCLC patients, cfDNA & cfRNA extraction and double detection for driver gene mutations was validated using the multi-gene mutations detection by RT-qPCR. RESULTS: Under the optimal protection system, 91.0% (101/111) of cfRNA were protected effectively. Among the 84 NSCLC patient samples, seven cytological samples failed the tests. In comparison with tumor samples, the overall sensitivity and specificity of detecting driver genes of supernatant cfDNA and cfRNA were 93.8% (74/77) and 100% (77/77), respectively. Notably, when focusing exclusively on patients with fusion gene changes, both sensitivity and specificity reached 100% (11/11) for EML4-ALK, ROS1, RET fusions, and MET ex14 skipping. CONCLUSION: These findings suggest that cfDNA & cfRNA extraction and double detection strategy recommended in this study improve the accuracy of driver genes mutations test, especially for RNA-based assay.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Ácidos Nucleicos Libres de Células , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/diagnóstico , Ácidos Nucleicos Libres de Células/genética , Mutación , Masculino , Femenino , Biomarcadores de Tumor/genética , Sensibilidad y Especificidad , Persona de Mediana Edad , Anciano , Proteínas de Fusión Oncogénica/genética , Proteínas Tirosina Quinasas , Proteínas Proto-OncogénicasRESUMEN
MitoAMPK was proved to inhibit the Warburg effect, but the specific mechanisms on non-small-cell lung cancer remain unclear. Here, we selected SIRT6 and MZF1 to clarify the mechanism. By western blotting, quantitative polymerase chain reaction, the CCK-8 assay, and immunohistochemistry assays, we found SIRT6 expression was lower in NSCLC tissues and cell lines than normal tissues and cells. Moreover, SIRT6 could inhibit the Warburg effect by regulating glycolysis-related genes of SLC2A2, SLC2A4 and PKM2. Finally, we demonstrated the interaction between SIRT6 and MZF1 using ChIP-qPCR. In conclusion, mitoAMPK inhibits the Warburg effect by regulating the expression of the MZF1-SIRT6 complex.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Regulación Neoplásica de la Expresión Génica , Factores de Transcripción de Tipo Kruppel , Neoplasias Pulmonares , Sirtuinas , Efecto Warburg en Oncología , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Sirtuinas/metabolismo , Sirtuinas/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Línea Celular Tumoral , Glucólisis/genética , Femenino , MasculinoRESUMEN
Acquired resistance is inevitable in the treatment of non-small cell lung cancer (NSCLC) with osimertinib, and one of the primary mechanisms responsible for this resistance is the epithelial-mesenchymal transition (EMT). We identify upregulation of the proviral integration site for Moloney murine leukemia virus 1 (PIM1) and functional inactivation of glycogen synthase kinase 3ß (GSK3ß) as drivers of EMT-associated osimertinib resistance. Upregulation of PIM1 promotes the growth, invasion, and resistance of osimertinib-resistant cells and is significantly correlated with EMT molecules expression. Functionally, PIM1 suppresses the ubiquitin-proteasome degradation of snail family transcriptional repressor 1 (SNAIL) and snail family transcriptional repressor 2 (SLUG) by deactivating GSK3ß through phosphorylation. The stability and accumulation of SNAIL and SLUG facilitate EMT and encourage osimertinib resistance. Furthermore, treatment with PIM1 inhibitors prevents EMT progression and re-sensitizes osimertinib-resistant NSCLC cells to osimertinib. PIM1/GSK3ß signaling is activated in clinical samples of osimertinib-resistant NSCLC, and dual epidermal growth factor receptor (EGFR)/PIM1 blockade synergistically reverse osimertinib-resistant NSCLC in vivo. These data identify PIM1 as a driver of EMT-associated osimertinib-resistant NSCLC cells and predict that PIM1 inhibitors and osimertinib combination therapy will provide clinical benefit in patients with EGFR-mutant NSCLC.
Asunto(s)
Acrilamidas , Compuestos de Anilina , Carcinoma de Pulmón de Células no Pequeñas , Resistencia a Antineoplásicos , Transición Epitelial-Mesenquimal , Receptores ErbB , Glucógeno Sintasa Quinasa 3 beta , Neoplasias Pulmonares , Proteínas Proto-Oncogénicas c-pim-1 , Transducción de Señal , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Acrilamidas/farmacología , Acrilamidas/uso terapéutico , Proteínas Proto-Oncogénicas c-pim-1/metabolismo , Proteínas Proto-Oncogénicas c-pim-1/genética , Transición Epitelial-Mesenquimal/efectos de los fármacos , Transición Epitelial-Mesenquimal/genética , Compuestos de Anilina/farmacología , Compuestos de Anilina/uso terapéutico , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Glucógeno Sintasa Quinasa 3 beta/genética , Receptores ErbB/metabolismo , Receptores ErbB/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Resistencia a Antineoplásicos/genética , Resistencia a Antineoplásicos/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Animales , Ratones , Línea Celular Tumoral , Mutación/genética , Ratones Desnudos , Factores de Transcripción de la Familia Snail/metabolismo , Factores de Transcripción de la Familia Snail/genética , Indoles , PirimidinasRESUMEN
KIFC3 is a member of the Kinesin superfamily proteins (KIFs). The role of KIFC3 in non-small cell lung cancer (NSCLC) is unknown. This study aimed to elucidate the function of KIFC3 in NSCLC and the underlying mechanism. Immunohistochemistry indicated that KIFC3 was highly expressed in NSCLC tissues and correlated with the degree of differentiation, tumor size, lymph node metastasis and TNM stage. MTT, colony formation and Transwell assays demonstrated that KIFC3 overexpression promoted the proliferation, migration and invasion of NSCLC cells in vitro, while KIFC3 knockdown led to the opposite results. The protein expression levels of PI3Kp85α and p-Akt were increased after KIFC3 overexpression, meanwhile the downstream protein expression levels such as cyclin D1, CDK4, CDK6, RhoA, RhoC and MMP2 were increased. This promotion effect could be inhibited by a specific inhibitor of the PI3K/Akt pathway, LY294002. Co-immunoprecipitation assays confirmed the interaction between endogenous/exogenous KIFC3 and PI3Kp85α. Tumor formation experiments in nude mice confirmed that KIFC3 overexpression promoted the proliferation, migration and invasion of NSCLC cells in vivo and performed its biological function through the PI3K/Akt signaling pathway.In conclusion, KIFC3 promotes the malignant behavior of NSCLC cells through the PI3K/Akt signaling pathway.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Movimiento Celular , Proliferación Celular , Neoplasias Pulmonares , Invasividad Neoplásica , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/genética , Humanos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Movimiento Celular/genética , Animales , Fosfatidilinositol 3-Quinasas/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/genética , Femenino , Masculino , Ratones , Línea Celular Tumoral , Persona de Mediana Edad , Cinesinas/metabolismo , Cinesinas/genética , Ratones Desnudos , Regulación Neoplásica de la Expresión GénicaRESUMEN
Non-small cell lung cancer (NSCLC) patients infected with COVID-19 experience much worse prognosis. However, the specific mechanisms behind this phenomenon remain unclear. We conducted a multicentre study, collecting surgical tissue samples from a total of 36 NSCLC patients across three centres to analyse. Among the 36 lung cancer patients, 9 were infected with COVID-19. COVID-19 infection (HR = 21.62 [1.58, 296.06], p = 0.021) was an independent risk factor of progression-free survival (PFS). Analysis of RNA-seq data of these cancer tissues demonstrated significantly higher expression levels of cuproptosis-associated genes in COVID-19-infected lung cancer patients. Using Lasso regression and Cox regression analysis, we identified 12 long noncoding RNAs (lncRNA) regulating cuproptosis. A score based on these lncRNA were used to divide patients into high-risk and low-risk groups. The results showed that the high-risk group had lower overall survival and PFS compared to the low-risk group. Furthermore, Tumor Immune Dysfunction and Exclusion (TIDE) database revealed that the high-risk group benefited more from immunotherapy. Drug sensitivity analysis identified cetuximab and gefitinib as potentially effective treatments for the high-risk group. Cuproptosis plays a significant role NSCLC patients infected with COVID-19. Promisingly, cetuximab and gefitinib have shown potential effectiveness for managing these patients.
Asunto(s)
COVID-19 , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , ARN Largo no Codificante , SARS-CoV-2 , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/complicaciones , Carcinoma de Pulmón de Células no Pequeñas/virología , COVID-19/genética , COVID-19/complicaciones , COVID-19/virología , ARN Largo no Codificante/genética , Masculino , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/virología , Neoplasias Pulmonares/complicaciones , Femenino , Persona de Mediana Edad , Pronóstico , Anciano , SARS-CoV-2/genética , Regulación Neoplásica de la Expresión GénicaRESUMEN
Emerging evidence demonstrates that curcumin has an inhibitory effect on non-small cell lung cancer (NSCLC), and its targets and mechanism of action need further exploration. The goal of this study was to explore the potential targets and mechanism of curcumin against NSCLC by network pharmacology, bioinformatics, and experimental validation, thereby providing more insight into combination treatment with curcumin for NSCLC in preclinical and clinical research. Curcumin targets against NSCLC were predicted based on HIT2.0, STD, CTD, and DisGeNET, and the core targets were analyzed via protein-protein interaction network construction (PPI), Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and molecular docking. The gene expression levels of samples in A549 cells, NCI-H460, and curcumin treated groups were detected by real-time quantitative PCR. A total of 67 common targets between curcumin and NSCLC were collected by screening public databases. GO and KEGG analysis suggested that curcumin treatment of NSCLC mainly involves cancer-related pathways, such as PI3K-AKT signaling pathway, Foxo signaling pathway, microRNAs, MAPK signaling pathway, HIF-1 signaling pathway, etc. The targets with the highest degree were identified through the PPI network, namely CASP3, CTNNB1, JUN, IL6, MAPK3, HIF1A, STAT3, AKT1, TP53, CCND1, VEGFA, and EGFR. The results of the in vitro experiments showed that curcumin treatment of NSCLC down-regulated the gene expressions of CCND1, CASP3, HIF1A, IL-6, MAPK3, STAT3, AKT1, and TP53. Our findings revealed that curcumin functions as a potential therapeutic candidate for NSCLC by suppressing multiple signaling pathways and interacting with multiple gene targets.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Biología Computacional , Curcumina , Neoplasias Pulmonares , Simulación del Acoplamiento Molecular , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Humanos , Curcumina/farmacología , Curcumina/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Mapas de Interacción de Proteínas/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Transducción de Señal/efectos de los fármacos , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Reacción en Cadena en Tiempo Real de la PolimerasaAsunto(s)
Carcinoma de Pulmón de Células no Pequeñas , ADN Tumoral Circulante , Neoplasias Pulmonares , Mutación , Proteínas Proto-Oncogénicas p21(ras) , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/sangre , Proteínas Proto-Oncogénicas p21(ras)/genética , ADN Tumoral Circulante/genética , ADN Tumoral Circulante/sangre , Piridinas/uso terapéutico , Piperazinas , PirimidinasAsunto(s)
Carcinoma de Pulmón de Células no Pequeñas , ADN Tumoral Circulante , Neoplasias Pulmonares , Mutación , Proteínas Proto-Oncogénicas p21(ras) , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/sangre , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/sangre , Proteínas Proto-Oncogénicas p21(ras)/genética , ADN Tumoral Circulante/genética , ADN Tumoral Circulante/sangre , Piridinas/uso terapéutico , Piperazinas , PirimidinasRESUMEN
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the standard of care for the management of EGFR-mutated non-small cell lung cancer. Recent results from the HARMONi-A trial lead to considering ivonescimab-a first-in-class, bispecific antibody targeting PD-1 and VEGF-plus chemotherapy as a new second-line option following third-generation TKIs.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Receptores ErbB , Neoplasias Pulmonares , Mutación , Inhibidores de Proteínas Quinasas , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamiento farmacológico , Receptores ErbB/genética , Receptores ErbB/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Anticuerpos Biespecíficos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
DNA ligase 1 (LIG1) plays a key role in DNA synthesis and DNA damage repair pathways. LIG1 has been shown to be up-regulated in human non-small cell lung cancer (NSCLC); however, its role and molecular regulatory mechanism in NSCLC cell proliferation are still not fully understand. In this study, we aimed to explore the role of LIG1 and post-transcripional regulators in NSCLC. Utilizing bioinformatic tools and qRT-PCR, our investigation substantiated the up-regulation of LIG1 within NSCLC cell lines and tumour tissues. Remarkably, individuals exhibiting elevated levels of LIG1 had diminished survival rates. Functionally, the depletion of LIG1 inhibited cell proliferation and migration, contrasting with the increased proliferation and migration upon LIG1 over-expression. Prediction from the TargetScanHuman database and results of dual luciferase reporter assays indicated that miR-325 could directly bind to and negatively regulate LIG1. Moreover, our findings demonstrated that the mimicry of miR-325 decreased cell viability, whereas its inhibition correspondingly increased viability, indicative of the tumour-suppressive role of miR-325 through the down-regulation of LIG1. Collectively, our findings show that LIG1 could promote tumour progression and knockdown of LIG1 could exert suppressive effects on NSCLC. As the post-transcriptional factor of LIG1, miR-325 could negatively regulate the expression of LIG1 to inhibit tumour progression in vitro. These findings suggest that LIG1 and miR-325 might be potential therapeutic targets for NSCLC treatment.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Movimiento Celular , Proliferación Celular , ADN Ligasa (ATP) , Neoplasias Pulmonares , MicroARNs , Femenino , Humanos , Masculino , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Línea Celular Tumoral , ADN Ligasa (ATP)/metabolismo , ADN Ligasa (ATP)/genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , MicroARNs/genética , MicroARNs/metabolismoRESUMEN
Non-small cell lung cancer (NSCLC) constitutes a significant portion of lung cancers and cytotoxic drugs (e.g. cisplatin) are currently the first-line treatment. However, NSCLC has developed resistance to this drug, which limits the therapeutic effect and thus affects prognosis. NSCLC sc-RNA-seq data were downloaded from the GEO database and Ku Leuven Laboratory for Functional Epigenetics, and bulk RNA-seq data were obtained from the TCGA database. The "Seurat" package was employed for scRNA-seq data processing, and the uniform manifold approximation and projection (UMAP) were applied for downscaling and cluster identification. Use the FindAllMarkers function to find differential genes (DEGs) for tumor stem cells. Then, we performed univariate regression analyses on the DEGs to identify potential prognostic genes. We created a machine learning framework based on potential prognostic genes, which combines 10 machine learning methods and their 101 combinations to get the optimal prognostic risk model. The model was evaluated in the training set and validation set. A nomogram was developed to provide physicians with a quantitative tool for prognosis prediction. Finally, we evaluated the expression and functionality of SLC2A1. We discovered 22 cell clusters containing 218379 cells by examining single-cell RNA sequencing datasets (GSE148071, KU_lom, GSE131907, GSE136246, GSE127465). Tumour cells were isolated for subpopulation analysis and 162 differential genes from SOX2_cancer were obtained. After univariate Cox analysis, we found 23 genes with prognostic potential prognostic value and utilized them to develop 101combination machine learning computational framework. We eventually picked the best performing 'StepCox[both] + RSF', which includes 8 genes. The model has a relatively high prediction accuracy in both TCGA and GEO datasets. In in vitro investigations, targeted suppression of the SLC2A1 gene resulted in significant reductions in proliferation, invasion and migration in A549 cells. In addition, a significant reduction in cisplatin resistance was seen in A549/DDP cells. The outcomes demonstrated the precision and credibility of the prognostic model for NSCLC, highlighting its potential significance in the treatment and prognosis of individuals affected by this disease. SLC2A1 may become a promising prognostic marker and a potential therapeutic target, offering valuable insights to inform clinical treatment decisions.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares , Aprendizaje Automático , Células Madre Neoplásicas , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Pronóstico , Biomarcadores de Tumor/genética , Perfilación de la Expresión Génica/métodosRESUMEN
BACKGROUND: Lung cancer, particularly non-small cell lung cancer (NSCLC), remains a significant cause of cancer-related mortality, with drug resistance posing a substantial obstacle to effective therapy. LncRNAs have emerged as pivotal regulators of NSCLC progression, suggesting potential targets for cancer diagnosis and treatment. Therefore, identifying new lncRNAs as therapeutic targets and comprehending their underlying regulatory mechanisms are crucial for treating NSCLC. MATERIALS AND METHODS: RNA-sequencing data from 149 lung adenocarcinoma (LUAD) patients, including 130 responders and 19 nonresponders to primary treatment, were analyzed to identify the most effective lncRNAs. The effects and regulatory pathways of the selected lncRNAs on NSCLC and cisplatin resistance were investigated. RESULTS: Glioblastoma-downregulated RNA (GLIDR) was the most effective lncRNA in nonresponsive NSCLC patients undergoing primary treatment, and it was highly expressed in NSCLC patients and those with cisplatin-resistant NSCLC. Reducing GLIDR expression enhanced cisplatin sensitivity in resistant NSCLC and decreased the malignant characteristics of NSCLC. Moreover, bioinformatic analysis and luciferase assays revealed that microRNA-342-5p (miR-342-5p) directly targets GLIDR. MiR-342-5p overexpression inhibited NSCLC cell proliferation, migration, and invasion, whereas miR-342-5p inhibition promoted NSCLC malignancy, which was rescued by suppressing GLIDR. Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PPARGC1A) was identified as a downstream target of miR-342-5p. PPARGC1A inhibition increased cisplatin sensitivity in resistant NSCLC. Moreover, PPARGC1A inhibition suppresses NSCLC malignancy, whereas PPARGC1A overexpression promoted it. Furthermore, GLIDR overexpression was found to counteract the inhibitory effects of miR-342-5p on PPARGC1A, and increased PPARGC1A expression reversed the inhibition of NSCLC malignancies caused by decreased GLIDR. CONCLUSIONS: GLIDR is a prognostic marker for cisplatin treatment in NSCLC and a therapeutic target in cisplatin-resistant NSCLC. GLIDR promotes NSCLC progression by sponging miR-342-5p to regulate PPARGC1A expression and regulates cisplatin resistance through the miR-342-5p/PPARGC1A axis, underscoring its potential as a therapeutic target in cisplatin-resistant NSCLC.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Proliferación Celular , Cisplatino , Resistencia a Antineoplásicos , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares , MicroARNs , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , ARN Largo no Codificante , Humanos , Cisplatino/farmacología , Cisplatino/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , MicroARNs/genética , Resistencia a Antineoplásicos/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , ARN Largo no Codificante/genética , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Femenino , Masculino , Animales , Ratones , Movimiento Celular/genética , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Persona de Mediana EdadRESUMEN
Circular RNAs (circRNAs) have played an essential role in cancer development. This study aimed to illustrate the impact and potential mechanism of circRACGAP1 action in NSCLC development. The expression patterns of circRACGAP1, miR-1296, and CDK2 in NSCLC tissues and cell lines were analysed by RT-qPCR. The function of circRACGAP1 in NSCLC cell proliferation and apoptosis was investigated using the CCK-8 assay, flow cytometry, TUNEL staining, and Western blot. The interaction among circRACGAP1, miR-1296, and CDK2 was clarified by dual-luciferase reporter assay while the correlation was confirmed by the Pearson correlation coefficient. The expression of circRACGAP1 and CDK2 was up-regulated in NSCLC tissues, while the expression of miR-1296 was down-regulated. Cell function studies further revealed that circRACGAP1 could promote NSCLC cell proliferation, accelerate the cell cycle process, up-regulate B-cell lymphoma 2 (Bcl2) expression, and down-regulate Bcl2-associated X (Bax) expression. miR-1296 was identified as a downstream target to reverse circRACGAP1-mediated cell proliferation. miR-1296 directly targeted the 3'-UTR of CDK2 to regulate proliferation and apoptosis of NSCLC cells. Additionally, the dual-luciferase reporter assay and Pearson correlation coefficient analysis proved that circRACGAP1 acted in NSCLC cells by negatively regulating miR-1296 expression and positively regulating CDK2 expression. In summary, our study revealed that circRACGAP1 promoted NSCLC cell proliferation by regulating the miR-1296/CDK2 pathway, providing potential diagnostic and therapeutic targets for NSCLC.
Asunto(s)
Apoptosis , Carcinoma de Pulmón de Células no Pequeñas , Proliferación Celular , Quinasa 2 Dependiente de la Ciclina , Neoplasias Pulmonares , MicroARNs , ARN Circular , Humanos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Proliferación Celular/genética , Quinasa 2 Dependiente de la Ciclina/metabolismo , Quinasa 2 Dependiente de la Ciclina/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Línea Celular Tumoral , ARN Circular/genética , ARN Circular/metabolismo , Apoptosis/genética , Regulación Neoplásica de la Expresión Génica , Transducción de Señal/genética , Proteínas Activadoras de GTPasa/genética , Proteínas Activadoras de GTPasa/metabolismoRESUMEN
Drug resistance is a major hurdle prohibiting effective treatment of many diseases, including cancer. Using model-guided designs, Leighow et al.1 engineered a dual-switch selection gene drive system custom designed to combat drug-resistant tumors. By demonstrating remarkable killing efficacies in preclinical models using human non-small lung cancer cells in vitro and in mice, this work describes an attractive mindset to develop next-generation anticancer therapies.