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1.
Anal Chem ; 93(34): 11719-11728, 2021 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-34415741

RESUMO

Membrane protein immobilization is particularly significant in in vitro drug screening and determining drug-receptor interactions. However, there are still some problems in the immobilization of membrane proteins with controllable direction and high conformational stability, activity, and specificity. Cell membrane chromatography (CMC) retains the complete biological structure of membrane proteins. However, conventional CMC has the limitation of poor stability, which results in its limited life span and low reproducibility. To overcome this limitation, we propose a method for the specific covalent immobilization of membrane proteins in cell membranes. We used the SNAP-tag as an immobilization tag fused to the epidermal growth factor receptor (EGFR), and Cys145 located at the active site of the SNAP-tag reacted with the benzyl group of O6-benzylguanine (BG). The SNAP-tagged EGFR was expressed in HEK293 cells. We captured the SNAP-tagged EGFR from the cell membrane suspension onto a BG-derivative-modified silica gel. Our immobilization strategy improved the life span and specificity of CMC and minimized loss of activity and nonspecific attachment of proteins. Next, a SNAP-tagged EGFR/CMC online HPLC-IT-TOF-MS system was established to screen EGFR antagonists from Epimedii folium. Icariin, magnoflorine, epimedin B, and epimedin C were retained in this model, and pharmacological assays revealed that magnoflorine could inhibit cancer cell growth by targeting the EGFR. This EGFR immobilization method may open up possibilities for the immobilization of other membrane proteins and has the potential to serve as a useful platform for screening receptor-binding leads from natural medicinal herbs.


Assuntos
Receptores ErbB , Tecnologia , Membrana Celular , Receptores ErbB/genética , Células HEK293 , Humanos , Reprodutibilidade dos Testes
2.
Medicine (Baltimore) ; 100(34): e27038, 2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34449486

RESUMO

ABSTRACT: Whether programmed death-ligand 1 (PD-L1) expression could predict the outcome of tyrosine kinase inhibitor (TKI) treatment and prognosis of epidermal growth factor receptor (EGFR)-mutant nonsmall cell lung cancer (NSCLC) is remaining controversial.Potential studies were search from PubMed, Embase, and Web of Science databases. Pooled odds ratio of objective response rate was used to describe the relationship between PD-L1 expression and primary resistance to EGFR-TKIs. Pooled hazard ratios (HRs) of progression-free survival (PFS) and overall survival (OS) were included to assess the effects of PD-L1 status on the outcome of EGFR-TKI treatment and survival of EGFR-mutant NSCLCs.Eighteen eligible studies (1986 EGFR-mutant NSCLCs) were included in this meta-analysis. Positive PD-L1 expression correlated with lower objective response rate of EGFR-TKI treatment (odds ratio [95% confidence interval {CI}] = 0.52 [0.28-0.98], P = .043), while PFS (adjusted HR [95% CI] = 1.49 [0.96-1.89], P = .332) and OS (HR [95% CI] = 1.24 [0.70-2.20], P = .456) of EGFR-TKI treatment did not correlated with PD-L1 status. Furthermore, PD-L1 expression was not a predictive biomarker for the OS (HR [95% CI] = 1.43 [0.98-2.08], P = .062) in overall EGFR-mutant cohort.Positive PD-L1 expression indicated a higher incidence of primary resistance, but did not correlate with the PFS or OS of EGFR-TKI therapy. In addition, PD-L1 expression was unlikely a predictive biomarker for prognosis of EGFR-mutant NSCLCs.


Assuntos
Antígeno B7-H1/biossíntese , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Estudos Observacionais como Assunto , Intervalo Livre de Progressão , Análise de Sobrevida
3.
Mol Cell ; 81(16): 3339-3355.e8, 2021 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-34352206

RESUMO

Cancer cells selectively promote translation of specific oncogenic transcripts to facilitate cancer survival and progression, but the underlying mechanisms are poorly understood. Here, we find that N7-methylguanosine (m7G) tRNA modification and its methyltransferase complex components, METTL1 and WDR4, are significantly upregulated in intrahepatic cholangiocarcinoma (ICC) and associated with poor prognosis. We further reveal the critical role of METTL1/WDR4 in promoting ICC cell survival and progression using loss- and gain-of-function assays in vitro and in vivo. Mechanistically, m7G tRNA modification selectively regulates the translation of oncogenic transcripts, including cell-cycle and epidermal growth factor receptor (EGFR) pathway genes, in m7G-tRNA-decoded codon-frequency-dependent mechanisms. Moreover, using overexpression and knockout mouse models, we demonstrate the crucial oncogenic function of Mettl1-mediated m7G tRNA modification in promoting ICC tumorigenesis and progression in vivo. Our study uncovers the important physiological function and mechanism of METTL1-mediated m7G tRNA modification in the regulation of oncogenic mRNA translation and cancer progression.


Assuntos
Colangiocarcinoma/genética , Proteínas de Ligação ao GTP/genética , Metiltransferases/genética , Biossíntese de Proteínas , Animais , Carcinogênese/genética , Colangiocarcinoma/patologia , Progressão da Doença , Receptores ErbB/genética , Guanosina/análogos & derivados , Guanosina/genética , Humanos , Camundongos , Processamento Pós-Transcricional do RNA/genética , RNA Mensageiro/genética , RNA de Transferência/genética
4.
Nat Commun ; 12(1): 4789, 2021 08 09.
Artigo em Inglês | MEDLINE | ID: mdl-34373451

RESUMO

CRISPR-based cancer dependency maps are accelerating advances in cancer precision medicine, but adequate functional maps are limited to the most common oncogenes. To identify opportunities for therapeutic intervention in other rarer subsets of cancer, we investigate the oncogene-specific dependencies conferred by the lung cancer oncogene, RIT1. Here, genome-wide CRISPR screening in KRAS, EGFR, and RIT1-mutant isogenic lung cancer cells identifies shared and unique vulnerabilities of each oncogene. Combining this genetic data with small-molecule sensitivity profiling, we identify a unique vulnerability of RIT1-mutant cells to loss of spindle assembly checkpoint regulators. Oncogenic RIT1M90I weakens the spindle assembly checkpoint and perturbs mitotic timing, resulting in sensitivity to Aurora A inhibition. In addition, we observe synergy between mutant RIT1 and activation of YAP1 in multiple models and frequent nuclear overexpression of YAP1 in human primary RIT1-mutant lung tumors. These results provide a genome-wide atlas of oncogenic RIT1 functional interactions and identify components of the RAS pathway, spindle assembly checkpoint, and Hippo/YAP1 network as candidate therapeutic targets in RIT1-mutant lung cancer.


Assuntos
Neoplasias Pulmonares/genética , Oncogenes/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Ciclo Celular/genética , Linhagem Celular Tumoral , Receptores ErbB/genética , Feminino , Técnicas de Inativação de Genes , Ensaios de Triagem em Larga Escala , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Camundongos , Terapia de Alvo Molecular , Mutação , Células NIH 3T3 , Proteínas Proto-Oncogênicas p21(ras)/genética , Fatores de Transcrição/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas ras
5.
In Vivo ; 35(5): 2569-2576, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34410944

RESUMO

BACKGROUND/AIM: The combination of regorafenib with cisplatin/pemetrexed has indicated controllable safety and encouraging antitumor activity in non-small cell lung cancer (NSCLC) patients. However, the anti-NSCLC effects and action mechanisms of regorafenib combined with cisplatin is ambiguous. The major goal of the study was to study the inhibitory effects and action mechanisms of regorafenib combined with cisplatin in NSCLC cells. MATERIALS AND METHODS: Cell viability, flow cytometry, immunofluorescence staining, western blotting, migration, and invasion assays were employed to verify the anti-NSCLC effects and mechanisms of regorafenib in combination with cisplatin. RESULTS: Cisplatin-induced epidermal growth factor receptor (EGFR)/nuclear factor κB (NF-κB) signaling was effectively inhibited by regorafenib treatment. Regorafenib, erlotinib (EGFR inhibitor) and QNZ (NF-κB inhibitor) may all enhance the cytotoxicity effect of cisplatin. The invasion ability was effectively decreased by combination treatment. Caspase-dependent and -independent apoptosis was activated by cisplatin combined with regorafenib. CONCLUSION: Apoptosis induction and EGFR/NF-κB inactivation correlate with regorafenib-enhanced anti-NSCLC efficacy of cisplatin. This study provides evidence of the therapeutic efficacy of regorafenib in combination with cisplatin on NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Apoptose , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células , Cisplatino , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , NF-kappa B/genética , Compostos de Fenilureia , Piridinas
6.
In Vivo ; 35(5): 2941-2945, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34410991

RESUMO

BACKGROUND: Osimertinib is a third-generation EGFR-tyrosine kinase inhibitor approved for the treatment of T790M-positive non-small-cell lung cancer. More recently, osimertinib demonstrated improved disease control compared to other EGFR-TKIs. Multiple mechanisms of resistance have been described in T790M-positive patients who experienced treatment failure with osimertinib. CASE REPORT: We report the case of a 78-year-old non-smoker woman with stage IV EGFR L858R-positive lung adenocarcinoma presented with T790M mutation after five years of treatment with gefitinib. The patient was started on osimertinib, but after two and a half years of treatment experienced disease progression. The analyses of circulating tumor DNA using next-generation sequencing showed, together with the pre-existing T790M and exon 21 L858R, the presence of the EGFR C797G resistance mutation. CONCLUSION: Our case report revealed a rare EGFR-dependent acquired resistance mutation to osimertinib in circulating tumor DNA. Liquid biopsy appears to be a promising resource to understand the biology of osimertinib resistance by clonal evolution monitoring and the identification of novel resistance mechanisms.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Acrilamidas , Idoso , Compostos de Anilina , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/genética , Feminino , Humanos , Biópsia Líquida , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Inibidores de Proteínas Quinases/uso terapêutico
7.
Int J Mol Sci ; 22(16)2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34445227

RESUMO

Osimertinib is the latest generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor used for patients with EGFR-mutated non-small cell lung cancer (NSCLC). We aimed to explore the novel mechanisms of osimertinib by particularly focusing on EGFR-independent effects, which have not been well characterized. We explored the EGFR-independent effects of osimertinib on cell proliferation using NSCLC cell lines, an antibody array analysis, and the association between the action of osimertinib and the ephrin receptor B4 (EphB4). We also studied the clinicopathological significance of EphB4 in 84 lung adenocarcinoma patients. Osimertinib exerted significant inhibitory effects on cell growth and cell cycle progression by promoting the phosphorylation of p53 and p21 and decreasing cyclin D1 expression independently of EGFR. EphB4 was significantly suppressed by osimertinib and promoted cell growth and sensitivity to osimertinib. The EphB4 status in carcinoma cells was positively correlated with tumor size, T factor, and Ki-67 labeling index in all patients and was associated with poor relapse-free survival in EGFR mutation-positive patients. EphB4 is associated with the EGFR-independent suppressive effects of osimertinib on cell cycle and with a poor clinical outcome. Osimertinib can exert significant growth inhibitory effects in EGFR-mutated NSCLC patients with a high EphB4 status.


Assuntos
Acrilamidas/farmacologia , Adenocarcinoma de Pulmão , Compostos de Anilina/farmacologia , Carcinoma Pulmonar de Células não Pequenas , Ciclo Celular/efeitos dos fármacos , Neoplasias Pulmonares , Proteínas de Neoplasias/metabolismo , Receptor EphB4/metabolismo , Células A549 , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/mortalidade , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Ciclo Celular/genética , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Mutação , Proteínas de Neoplasias/genética , Receptor EphB4/genética
8.
Medicine (Baltimore) ; 100(29): e26650, 2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34398022

RESUMO

RATIONAL: Epidermal growth factor receptor (EGFR) 20 exon insertion is the second most common EGFR aberrations in non-small cell lung cancer (NSCLC). Despite some novel EGFR inhibitors, clinically obtainable management for this subset of patients remains an unmet need. there are no previous reports of upfront combination therapy with immunotherapy and chemotherapy for lung adenocarcinoma with brain metastasis harboring EGFR 20 insertion. PATIENT CONCERNS: A 56-year-old man who sought care for dry cough was diagnosed with lung adenocarcinoma with brain metastases indicating a poor prognosis. DIAGNOSIS: Next-generation sequencing of lung biopsied tissue revealed an EGFR exon 20 in-frame insertion (P772_H773insYNP+H773Y). INTERVENTIONS: The patient started treatment of pemetrexed and carboplatin plus programmed cell death-1 inhibitor sintilimab in November 2019. OUTCOMES: The patient achieved partial responses both intra- and extra-cranially. After 6 cycles of treatment, the patient accepted sintilimab plus pemetrexed every 3 weeks as maintenance therapy, which was well-tolerated without any toxicity and is still ongoing after 18 months since initiation of 1st-line treatment. LESSONS: This is the first case report of the clinical benefit of upfront immune checkpoint inhibitors (ICIs) plus chemotherapy for a brain metastatic NSCLC patient harboring EGFR exon 20 insertion mutation. Further study is needed to validate the predictor involved in responders to ICIs-based therapy with EGFR mutations.


Assuntos
Adenocarcinoma/terapia , Neoplasias Encefálicas/terapia , Neoplasias Pulmonares/terapia , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/secundário , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/secundário , Terapia Combinada , Receptores ErbB/genética , Humanos , Imunoterapia , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Resultado do Tratamento
9.
Int J Mol Sci ; 22(16)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34445544

RESUMO

Patients with advanced-stage non-small-cell lung cancer (NSCLC) are susceptible to malnutrition and develop folate deficiency (FD). We previously found that folate deprivation induces drug resistance in hepatocellular carcinoma; here, we assessed whether disrupted cytoplasmic folate metabolism could mimic FD-induced metastasis and affect the sensitivity of NSCLC cells to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). We examined whether cytosolic folate metabolism in NSCLC cells was disrupted by FD or the folate metabolism blocker pemetrexed for 1-4 weeks. Our results revealed an increase in NF-κB overexpression-mediated epithelial-mesenchymal transition biomarkers: N-cadherin, vimentin, matrix metalloproteinases (MMPs), SOX9, and SLUG. This finding suggests that the disruption of folate metabolism can drastically enhance the metastatic properties of NSCLC cells. Cytosolic FD also affected EGFR-TKI cytotoxicity toward NSCLC cells. Because SLUG and N-cadherin are resistance effectors against gefitinib, the effects of SLUG knockdown in folate antagonist-treated CL1-0 cells were evaluated. SLUG knockdown prevented SLUG/NF-κB/SOX9-mediated invasiveness and erlotinib resistance acquisition and significantly reduced pemetrexed-induced gelatinase activity and MMP gene expression. To summarize, our data reveal two unprecedented adverse effects of folate metabolism disruption in NSCLC cells. Thus, the folic acid status of patients with NSCLC under treatment can considerably influence their prognosis.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/secundário , Citoplasma/metabolismo , Resistencia a Medicamentos Antineoplásicos , Ácido Fólico/metabolismo , Neoplasias Pulmonares/patologia , Inibidores de Proteínas Quinases/farmacologia , Apoptose , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Movimento Celular , Proliferação de Células , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Mutação , Células Tumorais Cultivadas
10.
Int J Mol Sci ; 22(16)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34445562

RESUMO

Synaptonemal complex protein 3 (SCP3), a member of the Cor1 family, has been implicated in cancer progression, and therapeutic resistance, as well as cancer stem cell (CSC)-like properties. Previously, we demonstrated that SCP3 promotes these aggressive phenotypes via hyperactivation of the AKT signaling pathway; however, the underlying mechanisms responsible for SCP3-induced AKT activation remain to be elucidated. In this study, we demonstrated that the EGF-EGFR axis is the primary route through which SCP3 acts to activate AKT signaling. SCP3 triggers the EGFR-AKT pathway through transcriptional activation of EGF. Notably, neutralization of secreted EGF by its specific monoclonal antibody reversed SCP3-mediated aggressive phenotypes with a concomitant reversal of EGFR-AKT activation. In an effort to elucidate the molecular mechanisms underlying SCP3-induced transcriptional activation of EGF, we identified Jun activation domain-binding protein 1 (JAB1) as a binding partner of SCP3 using a yeast two-hybrid (Y2H) assay system, and we demonstrated that SCP3 induces EGF transcription through physical interaction with JAB1. Thus, our findings establish a firm molecular link among SCP3, EGFR, and AKT by identifying the novel roles of SCP3 in transcriptional regulation. We believe that these findings hold important implications for controlling SCP3high therapeutic-refractory cancer.


Assuntos
Complexo do Signalossomo COP9/metabolismo , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ligação a DNA/metabolismo , Resistencia a Medicamentos Antineoplásicos , Fator de Crescimento Epidérmico/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Peptídeo Hidrolases/metabolismo , Neoplasias do Colo do Útero/tratamento farmacológico , Complexo do Signalossomo COP9/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ligação a DNA/genética , Fator de Crescimento Epidérmico/genética , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Mutação , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Peptídeo Hidrolases/genética , Fosforilação , Domínios e Motivos de Interação entre Proteínas , Transdução de Sinais , Células Tumorais Cultivadas , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia
11.
J Transl Med ; 19(1): 372, 2021 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-34461927

RESUMO

BACKGROUND: Epidermal growth factor receptor (EGFR) and lanthionine synthetase C-like 2 (LanCL2) genes locate in the same amplicon, and co-amplification of EGFR and LANCL2 is frequent in glioblastoma. However, the prognostic value of LANCL2 and EGFR co-amplification, and their mRNA and protein expression in glioblastoma remain unclear yet. METHODS: This study analyzed the prognostic values of the copy number variations (CNVs), mRNA and protein expression of LANCL2 and EGFR in 575 glioblastoma patients in TCGA database and 100 glioblastoma patients in tumor banks of the Shenzhen Second People's Hospital and the Sun Yat-sen University Cancer Center. RESULTS: The amplification of LANCL2 or EGFR, and their co-amplification were frequent in glioblastoma of TCGA database and our tumor banks. A significant correlation was found between the CNVs of LANCL2 and EGFR (p < 0.001). CNVs of LANCL2 or EGFR were significantly correlated with IDH1/2 mutation but not MGMT promoter methylation. Multivariate analysis showed that LANCL2 amplification was significantly correlated with reduced overall survival (OS) in younger (< 60 years) glioblastoma patients of TCGA database (p = 0.043, HR = 1.657) and our tumor banks (p = 0.018, HR = 2.199). However, LANCL2 or EGFR amplification, and their co-amplification had no significant impact on OS in older (≥ 60 years) or IDH1/2-wild-type glioblastoma patients. mRNA and protein overexpression of LANCL2 and EGFR was also frequently found in glioblastoma. The mRNA expression rather than the protein expression of LANCL2 and EGFR was positively correlated (p < 0.001). However, mRNA or protein expression of EGFR and LANCL2 was not significantly correlated with OS of glioblastoma patients. The protein expression level of LANCL2, rather than EGFR, was elevated in relapsing glioblastoma, compared with newly diagnosed glioblastoma. In addition, the intracellular localization of LanCL2, not EGFR, was associated with the grade of gliomas. CONCLUSIONS: Taken together, amplification and mRNA overexpression of LANCL2 and EGFR, and their co-amplification and co-expression were frequent in glioblastoma patients. Our findings suggest that amplification of LANCL2 and EGFR were the independent diagnostic biomarkers for glioblastoma patients, and LANCL2 amplification was a significant prognostic factor for OS in younger glioblastoma patients.


Assuntos
Neoplasias Encefálicas , Receptores ErbB/genética , Glioblastoma , Proteínas de Membrana/genética , Proteínas de Ligação a Fosfato/genética , Idoso , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Variações do Número de Cópias de DNA/genética , Receptores ErbB/metabolismo , Glioblastoma/genética , Humanos , Mutação , Recidiva Local de Neoplasia , Prognóstico , RNA Mensageiro/genética
12.
J Int Med Res ; 49(8): 3000605211035005, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34396834

RESUMO

Targeted therapy in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) often fails because of drug resistance. Here, we report a 57-year-old male patient with stage IV small cell lung cancer (SCLC) transformation during targeted therapy. Chest computerized tomography (CT), hematoxylin and eosin histological examination, immunohistochemistry, allele refractory mutation system-based quantitative polymerase chain reaction analysis of EGFR point mutations, and next-generation sequencing were performed for diagnosis and therapeutic efficacy evaluation. A combination of chest CT, histological examination, and immunohistochemistry confirmed the initial NSCLC diagnosis. Next-generation sequencing detected only EGFR exon 19 deletion (ex19del) before treatment and later identified EGFR exon20p.T790M point mutation, EGFR amplification, myc proto-oncogene (MYC) amplification, retinoblastoma 1 (RB1) mutation, and tumor protein 53 (TP53) mutation. Histology and immunohistochemistry revealed transformation from NSCLC to SCLC during treatment, which eventually returned to NSCLC. Drug resistance to targeted therapy for patients with NSCLC frequently occurs because of EGFR exon20p.T790M point mutation, TP53 mutation, RB1 mutation, and MYC amplification. These mutations are also the major determining factors of NSCLC outcomes. Therefore, next-generation sequencing should be performed to confirm drug efficacy during targeted therapy for NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Mutação , Inibidores de Proteínas Quinases/farmacologia , Carcinoma de Pequenas Células do Pulmão/diagnóstico por imagem , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/genética
13.
Medicine (Baltimore) ; 100(32): e26911, 2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34397927

RESUMO

RATIONALE: With the recent advancements in molecular biology research, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have emerged as excellent therapies for patients with EGFR-mutant cancers. However, these patients inevitably develop cross-acquired resistance to EGFR-TKIs. Transformation to small-cell lung cancer (SCLC) is considered a rare resistance mechanism against EGFR-TKI therapy. Here, we report a case of TKI resistance due to SCLC transformation and demonstrate its mechanisms and clinical features. PATIENT CONCERNS: A 54-year-old Chinese man with a history of smoking for 40 years complained of an intermittent cough in March 2019. DIAGNOSIS: Transbronchial lung biopsy was performed on the basal segment of the left lower lobe, which confirmed lung adenocarcinoma. In January 2020, repeat biopsy was performed, and the results of immunohistochemistry (IHC) staining showed TTF-1 (+), CK7 (+), napsin A (+), syn (+), and CD56 (+), with a Ki-67 (+) index 80% of small cell carcinomas. Infiltrating adenocarcinomas and small cell carcinomas were observed. INTERVENTIONS: Icotinib (125 mg thrice daily) was administered as a first-line treatment from June 2019. We subsequently administered a chemotherapy regimen consisting of etoposide (180 mg, days 1-3) plus cisplatin (45 mg, days 1-3) every 3 weeks for 1 cycle after recurrence. As the patient could not tolerate further chemotherapy, he continued taking icotinib orally and received whole-brain radiotherapy 10 times to a total dose of 30 Gy after brain metastases. OUTCOMES: The patient relapsed after successful treatment with icotinib for 9 months. A partial response was achieved after 4 cycles of chemotherapy, and despite the brief success of chemotherapy, our patient exhibited brain metastasis and metastases of the eleventh thoracic spine and the second lumbar vertebra with pathological fracture. The patient eventually died of aggressive cancer progression. LESSONS: Our case highlights the possibility of SCLC transformation from EGFR-mutant adenocarcinoma and the importance of repeat biopsy for drug resistance. Serum neuron-specific enolase levels may also be useful for detecting early SCLC transformation.


Assuntos
Adenocarcinoma de Pulmão/genética , DNA de Neoplasias/genética , Neoplasias Pulmonares/genética , Mutação , Carcinoma de Pequenas Células do Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Biópsia , Transformação Celular Neoplásica , Análise Mutacional de DNA , Receptores ErbB/genética , Receptores ErbB/metabolismo , Evolução Fatal , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Carcinoma de Pequenas Células do Pulmão/diagnóstico , Carcinoma de Pequenas Células do Pulmão/metabolismo , Tomografia Computadorizada por Raios X
17.
Anticancer Res ; 41(8): 3997-4004, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34281864

RESUMO

BACKGROUND/AIM: The frequency of somatic mutations of epidermal growth factor receptor (EGFR) in primary lung adenocarcinoma varies among populations and countries. The aim of the present study was to clarify whether the frequency of EGFR mutations in patients with lung adenocarcinoma depends on their mitochondrial DNA haplogroup, which reflects their maternal lineage. PATIENTS AND METHODS: Using normal lung tissue specimens, the mitochondrial DNA haplogroup was determined by multiplex polymerase chain reaction in 135 Japanese patients who underwent surgery for primary lung adenocarcinoma. RESULTS: The 135 patients were divided into two groups according to the two primitive haplotypes (N group, n=32; M group, n=103). The frequency of EGFR mutations in the N group was significantly higher than that in the M group (69% vs. 48%, p=0.044). The difference was prominent when the analysis was restricted to non-smokers (95% vs. 57%, p<0.01). CONCLUSION: The frequency of EGFR mutations in lung adenocarcinoma patients depends on their mitochondrial lineage.


Assuntos
Adenocarcinoma de Pulmão/genética , Grupo com Ancestrais do Continente Asiático/genética , DNA Mitocondrial , Neoplasias Pulmonares/genética , Idoso , Receptores ErbB/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Fumar/genética
18.
Anticancer Res ; 41(8): 3741-3746, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34281832

RESUMO

BACKGROUND/AIM: Reports on over-expression of the epidermal growth factor receptor (EGFR) in bladder cancer and its function in tumorigenesis have suggested to target this antigen. MATERIALS AND METHODS: We generated the targeted toxin EGF-PE40 consisting of the human epidermal growth factor (EGF) as the binding domain and PE40, a truncated version of Pseudomonas Exotoxin A, as the toxin domain. EGF-PE40 was tested on EGFR-expressing bladder cancer cells in view of binding via flow cytometry, and cytotoxicity via WST viability assay. Induction of apoptosis was examined by western blot. RESULTS: The targeted toxin specifically triggered cytotoxicity in the bladder cancer cells with 50% inhibitory concentration (IC50) values in the low nanomolar or picomolar range, and was about 1,250- to 1,500-fold more cytotoxic than the EGFR inhibitor erlotinib. Cytotoxicity of EGF-PE40 was based on the induction of apoptosis. CONCLUSION: EGF-PE40 represents a promising candidate for the future treatment of bladder cancer.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Fator de Crescimento Epidérmico/química , Neoplasias da Bexiga Urinária/tratamento farmacológico , ADP Ribose Transferases/química , Animais , Toxinas Bacterianas/química , Células CHO , Linhagem Celular Tumoral , Cricetulus , Fator de Crescimento Epidérmico/genética , Fator de Crescimento Epidérmico/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Exotoxinas/química , Humanos , Fatores de Virulência/química
19.
Anticancer Res ; 41(7): 3409-3417, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230136

RESUMO

BACKGROUND/AIM: ER-positive breast cancer patients commonly undergo endocrine therapy with drugs such as tamoxifen. Despite tamoxifen being a highly effective drug, long-term treatment results in resistance in one-third of the patients. Although many explanations for the development of tamoxifen resistance have been put forward, a clearly defined underlying mechanism is still lacking. MATERIALS AND METHODS: The expression level of HOXB5 was evaluated between MCF7 breast cancer cells and tamoxifen-resistant MCF7 (TAMR) cells by RT-PCR. Then, the effect of HOXB5 on invasion and migration abilities as well as on cancer stemness were investigated through 3D culture and spheroid formation assay. RESULTS: In this study, we provide evidence that HOXB5 is up-regulated in TAMR cells. EGFR is concurrently overexpressed, and the EGFR signaling cascade is activated, resulting in migratory and invasive phenotypes in TAMR cells compared to MCF7 cells. However, HOXB5 knockdown in TAMR cells resulted in the de-activation of the EGFR signaling pathway, less aggressive phenotypes and restoration of sensitivity to tamoxifen treatment. More interestingly, TAMR cells expressed higher levels of stem cell markers, and as a result, their enhanced stemness allowed for a better formation of spheroids than MCF7 cells. When HOXB5 was overexpressed in MCF7 cells, they were able to form a larger number of spheroids as in TAMR cells. CONCLUSION: HOXB5 is one of the key factors involved in tumor aggression and progression in tamoxifen-resistant breast cancer cells.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Movimento Celular/genética , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Homeodomínio/genética , Biomarcadores Tumorais/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Progressão da Doença , Receptores ErbB/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Células MCF-7 , Transdução de Sinais/genética , Células-Tronco/patologia , Tamoxifeno/farmacologia
20.
World J Surg Oncol ; 19(1): 197, 2021 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-34217313

RESUMO

BACKGROUND: To analyze and evaluate EGFR, KRAS, and PIK3CA gene mutation rates and clinical distribution in patients with different types of lung cancer METHOD: A total of 221 lung cancer patients treated in our hospital between January 2016 and June 2019 were enrolled. Tissue and whole blood samples were collected and analyzed to determine the mutation status of EGFR, KRAS, and PIK3CA genes. The gene exon mutation rates were determined. Relevant clinical data, such as age, gender, tumor sample type, treatment method, pathologic type, and lung cancer stage were recorded and statistically analyzed. RESULTS: The EGFR gene mutation rates in exons E18-E21 were 2.3%, 17.6%, 3.6%, and 20.4%, respectively. E18, E19, and E20 mutations were commonly detected in adenosquamous carcinoma, and E21 mutations were commonly detected in adenocarcinoma. Mutations in exons E18-E21 were frequently detected in patients with lung cancer stages IA, IB, IIA, or IIB, respectively. The KRAS gene mutation rate in lung cancer patients in exon E2 was higher in whole blood and tissue samples than other exon mutations, while the KRAS gene mutation rate in exons E2 and E3 was significantly higher in patients with lung cancer stages IIB and IA, respectively. PIK3CA gene mutations in exons E9 and E20 occurred in patients < 60 years of age. Exon E9-positive mutations were more common in men or patients with squamous cell carcinoma, while exon E20-positive mutations were more common in females. CONCLUSION: The EGFR, KRAS, and PIK3CA gene exon mutation rates differ and were shown to be correlated with different clinical indicators, which have significance in clinical treatment.


Assuntos
Neoplasias Pulmonares , Taxa de Mutação , Classe I de Fosfatidilinositol 3-Quinases , Receptores ErbB/genética , Feminino , Sistemas de Distribuição no Hospital , Humanos , Masculino , Mutação , Prognóstico , Proteínas Proto-Oncogênicas p21(ras)
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