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1.
Medicine (Baltimore) ; 99(36): e22128, 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32899099

RESUMO

RATIONALE: Brain metastasis (BM) is a serious complication in non-small cell lung cancer (NSCLC) patients. Pemetrexed is one of the preferred agents in nonsquamous NSCLC with BM; however, the traditional chemotherapy demonstrated limited efficacy partly due to drug resistance and the blood-brain barrier. PATIENT CONCERNS: A 52-year-old male non-smoker was admitted for irritating cough, chest distress, and back pain. DIAGNOSES: Epidermal growth factor receptor wild-type, anaplastic lymphoma kinase-negative primary lung adenocarcinoma with an asymptomatic solitary BM (cTxNxM1b, IVA). INTERVENTIONS: Pemetrexed (500 mg/m of body surface area) and carboplatin (area under the curve of 5) were firstly administered every 3 weeks for 3 cycles, followed by pemetrexed/carboplatin plus anlotinib (12 mg daily; 2 weeks on and 1 week off) for another 3 cycles. Then maintenance anlotinib monotherapy was continued for a year, without unacceptable adverse events. OUTCOMES: The BM was slightly enlarged after 3 cycles of pemetrexed/carboplatin; however, a complete remission was achieved after the combination therapy. His intracranial progression-free survival was more than 2 years. LESSONS: Pemetrexed/carboplatin plus anlotinib could be considered for the treatment of epidermal growth factor receptor wild-type, anaplastic lymphoma kinase-negative lung adenocarcinoma with BM. Further well-designed trials are warranted to verify this occasional finding.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/secundário , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Quinase do Linfoma Anaplásico/metabolismo , Carboplatina/uso terapêutico , Receptores ErbB/genética , Receptores ErbB/metabolismo , Humanos , Indóis/uso terapêutico , Masculino , Pessoa de Meia-Idade , Pemetrexede/uso terapêutico , Quinolinas/uso terapêutico
2.
Nat Commun ; 11(1): 4607, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32929081

RESUMO

Drug tolerance is the basis for acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) including osimertinib, through mechanisms that still remain unclear. Here, we show that while AXL-low expressing EGFR mutated lung cancer (EGFRmut-LC) cells are more sensitive to osimertinib than AXL-high expressing EGFRmut-LC cells, a small population emerge osimertinib tolerance. The tolerance is mediated by the increased expression and phosphorylation of insulin-like growth factor-1 receptor (IGF-1R), caused by the induction of its transcription factor FOXA1. IGF-1R maintains association with EGFR and adaptor proteins, including Gab1 and IRS1, in the presence of osimertinib and restores the survival signal. In AXL-low-expressing EGFRmut-LC cell-derived xenograft and patient-derived xenograft models, transient IGF-1R inhibition combined with continuous osimertinib treatment could eradicate tumors and prevent regrowth even after the cessation of osimertinib. These results indicate that optimal inhibition of tolerant signals combined with osimertinib may dramatically improve the outcome of EGFRmut-LC.


Assuntos
Acrilamidas/uso terapêutico , Compostos de Anilina/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação/genética , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Receptor IGF Tipo 1/antagonistas & inibidores , Acrilamidas/farmacologia , Idoso de 80 Anos ou mais , Compostos de Anilina/farmacologia , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Receptores ErbB/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Fator 3-alfa Nuclear de Hepatócito/metabolismo , Humanos , Imidazóis/farmacologia , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Modelos Biológicos , Fosforilação/efeitos dos fármacos , Pirazinas/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Regulação para Cima/efeitos dos fármacos
3.
PLoS One ; 15(9): e0237802, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32976510

RESUMO

As availability of precision therapies expands, a well-validated circulating cell-free DNA (cfDNA)-based comprehensive genomic profiling assay has the potential to provide considerable value as a complement to tissue-based testing to ensure potentially life-extending therapies are administered to patients most likely to benefit. Additional data supporting the clinical validity of cfDNA-based testing is necessary to inform optimal use of these assays in the clinic. The FoundationOne®Liquid CDx assay is a pan-cancer cfDNA-based comprehensive genomic profiling assay that was recently approved by FDA. Validation studies included >7,500 tests and >30,000 unique variants across >300 genes and >30 cancer types. Clinical validity results across multiple tumor types are presented. Additionally, results demonstrated a 95% limit of detection of 0.40% variant allele fraction for select substitutions and insertions/deletions, 0.37% variant allele fraction for select rearrangements, 21.7% tumor fraction for copy number amplifications, and 30.4% TF for copy number losses. The limit of detection for microsatellite instability and blood tumor mutational burden were also determined. The false positive variant rate was 0.013% (approximately 1 in 8,000). Reproducibility of variant calling was 99.59%. In comparison with an orthogonal method, an overall positive percent agreement of 96.3% and negative percent agreement of >99.9% was observed. These study results demonstrate that FoundationOne Liquid CDx accurately and reproducibly detects the major types of genomic alterations in addition to complex biomarkers such as microsatellite instability, blood tumor mutational burden, and tumor fraction. Critically, clinical validity data is presented across multiple cancer types.


Assuntos
Bioensaio/métodos , Ácidos Nucleicos Livres/genética , Genômica , Neoplasias/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Receptores ErbB/genética , Éxons/genética , Humanos , Limite de Detecção , Mutação/genética , Intervalo Livre de Progressão , Reprodutibilidade dos Testes
4.
Anticancer Res ; 40(9): 5309-5311, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878822

RESUMO

BACKGROUND/AIM: Experimental studies have shown that celecoxib is related to the downregulation of Tregs and an increase in the therapeutic efficacy of PD-1 inhibitors; however, such effect has not been shown in human cancers. Our report confirmed the synergistic effect of celecoxib with a PD-1 inhibitor. CASE REPORT: A 57-year-old male with advanced pulmonary adenocarcinoma was treated with nivolumab monotherapy as 5th line sequential treatment. Although the patient experienced tumor remission, regrowth of the primary tumor was observed and he complained of lumbar pain. Therefore, celecoxib (400 mg/day) was initiated without cessation of nivolumab. Chest radiography revealed a marked shrinkage of the primary site, with a decreasing trend of carcinoma embryonic antigen. CONCLUSION: This is the report of a case of recovery of sensitivity to nivolumab by additional treatment with celecoxib.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Celecoxib/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Biomarcadores Tumorais , Celecoxib/administração & dosagem , Celecoxib/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/farmacologia , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Sinergismo Farmacológico , Receptores ErbB/genética , Humanos , Imunomodulação/efeitos dos fármacos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/etiologia , Masculino , Pessoa de Meia-Idade , Mutação , Radiografia Torácica , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Resultado do Tratamento
5.
Tokai J Exp Clin Med ; 45(3): 113-116, 2020 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-32901897

RESUMO

Mutations in the gene encoding epidermal growth factor receptor (EGFR) are the most frequent driver mutations in lung adenocarcinoma in Japan. Exon 19 deletion and L858R mutation in exon 21 are the most common EGFR mutations. Uncommon mutations, such as G719X, S768I, and L861Q, and compound mutations, combinations of 2 common or uncommon mutations, have also been reported. EGFR tyrosine kinase inhibitors (TKIs) are effective against cancers harboring common mutations; however, their efficacy against cancers with uncommon or compound mutations remains unclear. We report the case of a 67-year-old man with lung adenocarcinoma (clinical stage IIIA [cT1N2M0]), harboring an uncommon compound mutation, G719X and S768I. The cancer progressed within 2 months of initial chemoradiotherapy. Treatment with afatinib (40 mg/day) produced a partial response, which was maintained for 17 months with continued treatment. A literature review revealed that lung cancer with G719X/S768I compound mutation exhibited good response to EGFR-TKIs, even better than that of lung cancers with single uncommon mutations.


Assuntos
Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Afatinib/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Idoso , Receptores ErbB/genética , Éxons/genética , Deleção de Genes , Humanos , Masculino , Resultado do Tratamento
6.
Eur Rev Med Pharmacol Sci ; 24(16): 8606-8620, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32894568

RESUMO

OBJECTIVE: COVID-19 immune syndrome is a multi-systemic disorder induced by the COVID-19 infection. Pathobiological transitions and clinical stages of the COVID-19 syndrome following the attack of SARS-CoV-2 on the human body have not been fully explored. The aim of this review is to outline the three critical prominent phase regarding the clinicogenomics course of the COVID-19 immune syndrome. MATERIALS AND METHODS: In the clinical setting, the COVID-19 process presents as "asymptomatic/pre-symptomatic phase", "respiratory phase with mild/moderate/severe symptoms" and "multi-systemic clinical syndrome with impaired/disproportionate and/or defective immunity". The corresponding three genomic phases include the "ACE2, ANPEP transcripts in the initial phase", "EGFR and IGF2R transcripts in the propagating phase" and the "immune system related critical gene involvements of the complicating phase". RESULTS: The separation of the phases is important since the genomic features of each phase are different from each other and these different mechanisms lead to distinct clinical multi-systemic features. Comprehensive genomic profiling with next generation sequencing may play an important role in defining and clarifying these three unique separate phases for COVID-19. From our point of view, it is important to understand these unique phases of the syndrome in order to approach a COVID-19 patient bedside. CONCLUSIONS: This three-phase approach may be useful for future studies which will focus on the clinical management and development of the vaccines and/or specific drugs targeting the COVID-19 processes. ANPEP gene pathway may have a potential for the vaccine development. Regarding the specific disease treatments, MAS agonists, TXA127, Angiotensin (1-7) and soluble ACE2 could have therapeutic potential for the COVID-19 course. Moreover, future CRISPR technology can be utilized for the genomic editing and future management of the clinical course of the syndrome.


Assuntos
Doenças Assintomáticas , Infecções por Coronavirus/patologia , Sistema Imunitário/metabolismo , Pneumonia Viral/patologia , Betacoronavirus/isolamento & purificação , Infecções por Coronavirus/complicações , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Citocinas/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Regulação da Expressão Gênica , Humanos , Insuficiência de Múltiplos Órgãos/etiologia , Insuficiência de Múltiplos Órgãos/patologia , Pandemias , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/complicações , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Prognóstico , Receptor IGF Tipo 2/genética , Receptor IGF Tipo 2/metabolismo , Sepse/complicações , Sepse/patologia , Índice de Gravidade de Doença , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo
7.
Am J Clin Oncol ; 43(9): 670-675, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32889839

RESUMO

During the course of therapy, patients with small cell lung cancer have been noted to develop transformation to non-small cell lung cancer and conversely, patients with non-small cell lung cancer have had transformation to small cell lung cancer or other non-small cell histologies. Transformation may occur after prior tyrosine kinase inhibitors, chemotherapy, immunotherapy or radiation therapy. These changes reflect on the overlapping biology of these cell types and the clinical need for re-biopsy at times of disease progression. The optimum therapy after transformation will depend upon prior therapies received, the functional capacity of the patient, and further research to define the best therapy options.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Carcinoma de Pequenas Células do Pulmão/patologia , Quinase do Linfoma Anaplásico/genética , Biomarcadores Tumorais/sangue , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/terapia , Transformação Celular Neoplásica , Receptores ErbB/genética , Rearranjo Gênico , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Mutação , Nivolumabe/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/terapia
8.
Am J Chin Med ; 48(6): 1475-1489, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32907364

RESUMO

Inadequate responses to traditional chemotherapeutic agents in cholangiocarcinoma (CCA) emphasize a requirement for new effective compounds for the treatment of this malignancy. This study aimed to investigate the antiproliferative property of cucurbitacin B on KKU-100 CCA cells. The determination of underlying molecular mechanisms was also carried out. The results revealed that cucurbitacin B suppressed growth and replicative ability to form colonies of CCA cells, suggesting the antiproliferative effect of this compound against the cells. Flow cytometry analysis demonstrated that the interfering effect of cucurbitacin B on the CCA cell cycle at the G2/M phase was accountable for its antiproliferation property. Accompanied with cell cycle disruption, cucurbitacin B altered the expression of proteins involved in the G2/M phase transition including downregulation of cyclin A, cyclin D1, and cdc25A, and upregulation of p21. Additional molecular studies demonstrated that cucurbitacin B suppressed the activation of focal adhesion kinase (FAK) which consequently resulted in inhibition of its kinase-dependent and kinase-independent downstream targets contributing to the regulation of cell proliferation including PI3K/PDK1/AKT and p53 proteins. In this study, the transient knockdown of FAK using siRNA was employed to ascertain the role of FAK in CCA cell proliferation. Finally, the effect of cucurbitacin B on upstream receptor tyrosine kinases regulating FAK activation was elucidated. The results showed that the inhibitory effect of cucurbitacin B on FAK activation in CCA cells is mediated via interference of EGFR and HER2 expression. Collectively, cucurbitacin B might be a promising drug for CCA treatment by targeting FAK protein.


Assuntos
Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Quinase Piruvato Desidrogenase (Transferência de Acetil)/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Triterpenos/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Neoplasias dos Ductos Biliares/dietoterapia , Linhagem Celular Tumoral , Colangiocarcinoma/tratamento farmacológico , Receptores ErbB/genética , Receptores ErbB/metabolismo , Expressão Gênica/efeitos dos fármacos , Humanos , Terapia de Alvo Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Triterpenos/uso terapêutico
9.
Anticancer Res ; 40(10): 5757-5764, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988903

RESUMO

BACKGROUND/AIM: To describe real clinical outcomes in patients with non-small cell lung cancer who have uncommon epidermal growth factor receptor (EGFR) mutations. MATERIALS AND METHODS: We performed a retrospective chart review from 15 medical institutes that cover a population of three million people from April 2008 to March 2019. RESULTS: There were 102 patients with uncommon EGFR mutation. Progression-free survival (PFS) tended to be longer in patients receiving afatinib compared with first-generation EGFR tyrosine kinase inhibitors. PFS in patients treated with afatinib or osimertinib was significantly longer than in patients treated with gefitinib or erlotinib (p=0.030). Multivariate analysis also revealed the contribution of afatinib or osimertinib to increased survival. In patients with exon 20 insertions, chemotherapy was efficacious. CONCLUSION: In treating patients with uncommon EGFR mutations, our results indicate longer-term survival might be achieved with second-generation or later TKIs and cytotoxic chemotherapeutic drugs.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Acrilamidas/uso terapêutico , Adulto , Afatinib/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Cloridrato de Erlotinib/uso terapêutico , Feminino , Gefitinibe/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Intervalo Livre de Progressão
10.
PLoS One ; 15(8): e0238120, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32833992

RESUMO

PURPOSE: Conjunctival squamous cell carcinoma (SCC) is primarily treated with surgical resection. SCC has various stages, and local recurrence is common. The purpose of this study was to determine molecular localization of epidermal growth factor receptor (EGFR) and the possibility of EGFR as a biomarker for the management of conjunctival SCC. METHODS: In this retrospective study, we performed immunohistochemistry to evaluate EGFR expression and localization in tumor cells, EGFR mutation-specific expression (E746-A750del and L858R), and human papillomavirus expression in a series of 29 conjunctival SCCs. RESULTS: All 29 tumors in our cohort were EGFR positive (100%). Twenty-one of 29 tumors (72%) showed focal EGFR staining, and seven (28%) showed diffuse EGFR staining. In addition, we calculated the percentages of the two most important mutations in EGFR (exon 19 746-A750del (8/29, 27.5%), exon 21 (L858R mutant (2/29, 6.8%)) in conjunctival SCCs. We observed that the translocation of EGFR from the membrane into the cytoplasm was related to clinical prognosis, as we detected correlations between EGFR cytoplasmic staining and final orbital exenteration and between decreased EGFR membrane staining and progression-free survival. CONCLUSIONS: EGFR is important in the pathology of ocular surface squamous neoplasia including SCC and is a prognostic factor. Increased understanding of EGFR mutations may have important implications for future treatment options.


Assuntos
Carcinoma de Células Escamosas/genética , Neoplasias da Túnica Conjuntiva/genética , Adenocarcinoma/patologia , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/metabolismo , Estudos de Coortes , Neoplasias da Túnica Conjuntiva/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Neoplasias de Cabeça e Pescoço/genética , Humanos , Imuno-Histoquímica/métodos , Neoplasias Pulmonares/genética , Masculino , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia/genética , Prognóstico , Estudos Retrospectivos
11.
PLoS One ; 15(8): e0237790, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32810185

RESUMO

This study determined the frequency and factors associated with EGFR testing rates and erlotinib treatment as well as associated survival outcomes in patients with non small cell lung cancer in Kentucky. Data from the Kentucky Cancer Registry (KCR) linked with health claims from Medicaid, Medicare and private insurance groups were evaluated. EGFR testing and erlotinib prescribing were identified using ICD-9 procedure codes and national drug codes in claims, respectively. Logistic regression analysis was performed to determine factors associated with EGFR testing and erlotinib prescribing. Cox-regression analysis was performed to determine factors associated with survival. EGFR mutation testing rates rose from 0.1% to 10.6% over the evaluated period while erlotinib use ranged from 3.4% to 5.4%. Factors associated with no EGFR testing were older age, male gender, enrollment in Medicaid or Medicare, smoking, and geographic region. Factors associated with not receiving erlotinib included older age, male gender, enrollment in Medicare or Medicaid, and living in moderate to high poverty. Survival analysis demonstrated EGFR testing or erlotinib use was associated with a higher likelihood of survival. EGFR testing and erlotinib prescribing were slow to be implemented in our predominantly rural state. While population-level factors likely contributed, patient factors, including geographic location (areas with high poverty rates and rural regions) and insurance type, were associated with lack of use, highlighting rural disparities in the implementation of cancer precision medicine.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cloridrato de Erlotinib/uso terapêutico , Testes Genéticos/estatística & dados numéricos , Neoplasias Pulmonares/tratamento farmacológico , Demandas Administrativas em Assistência à Saúde/estatística & dados numéricos , Adulto , Fatores Etários , Idoso , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Análise Mutacional de DNA/economia , Análise Mutacional de DNA/estatística & dados numéricos , Prescrições de Medicamentos/economia , Prescrições de Medicamentos/estatística & dados numéricos , Uso de Medicamentos/economia , Uso de Medicamentos/estatística & dados numéricos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Feminino , Testes Genéticos/economia , Disparidades em Assistência à Saúde/economia , Humanos , Kentucky/epidemiologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Masculino , Medicaid/economia , Medicaid/estatística & dados numéricos , Medicare/economia , Medicare/estatística & dados numéricos , Pessoa de Meia-Idade , Mutação , Pobreza/estatística & dados numéricos , Medicina de Precisão/economia , Medicina de Precisão/estatística & dados numéricos , Sistema de Registros/estatística & dados numéricos , Estudos Retrospectivos , Fatores Sexuais , Análise de Sobrevida , Estados Unidos , Adulto Jovem
12.
Medicine (Baltimore) ; 99(34): e21826, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32846826

RESUMO

BACKGROUND: Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is the primary treatment in treating with EGFR mutant nonsmall cell lung cancer (NSCLC). This systematic review and meta-analysis aimed to evaluate the efficacy and safety of the third-generation EGFR-TKI, osimertinib, and summarize the risk factors associating with outcome after osimertinib treatment. METHOD: The Ovid Medline, Embase, Cochrane Library, and Pubmed were systematically searched due to December 10, 2019. All the studies that mentioned the overall survival (OS), progression-free survival (PFS), treatment response, and adverse events (AEs) of osimertinib were involved in our study. Hazard ratio (HR) with 95% confidence intervals was used for comparing OS and PFS. RESULT: A total of 47 studies were included in the systematic review, of which 14 studies were used to compare the efficacy between osimertinib and other EGFR-TKI or chemotherapy. Patients treating with osimertinib favors a higher OS and PFS in all the patients (HR = 0.56 and 0.38, P < .001, respectively), and in subgroup analysis, compared with other treatments. Median 55% T790 mutant NSCLC patients might experience partial response, and 25% of patients remained as stable disease. The incidence of severe AE ranged from 0% to 5%, and the most common severe AE was pneumonia (3%). Patients with the T858R mutation may have a better OS than Del 19 mutation (HR = 0.55, P = .037), while patients who have a smoking history may have a higher risk of progression than never-smoker patients (HR = 1.47, P = .028). CONCLUSION: Osimertinib has an impressive antitumor activity compared with prior EGFR-TKI and chemotherapy with an acceptable response and tolerable AEs. EGFR mutation type and smoking status were the risk factors for mortality and progression in NSCLC patients.


Assuntos
Acrilamidas/uso terapêutico , Compostos de Anilina/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Acrilamidas/efeitos adversos , Compostos de Anilina/efeitos adversos , Antineoplásicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/genética , Fumar Cigarros , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/genética , Mutação , Pneumonia/induzido quimicamente , Intervalo Livre de Progressão , Taxa de Sobrevida
13.
PLoS One ; 15(8): e0236580, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32756609

RESUMO

Lung cancer is generally treated with conventional therapies, including chemotherapy and radiation. These methods, however, are not specific to cancer cells and instead attack every cell present, including normal cells. Personalized therapies provide more efficient treatment options as they target the individual's genetic makeup. The goal of this study was to identify the frequency of causal genetic mutations across a variety of lung cancer subtypes in the earlier stages. 833 samples of non-small cell lung cancer from 799 patients who received resection of their lung cancer, were selected for molecular analysis of six known mutations, including EGFR, KRAS, BRAF, PIK3CA, HER2 and ALK. A SNaPshot assay was used for point mutations and fragment analysis searched for insertions and deletions. ALK was evaluated by IHC +/- FISH. Statistical analysis was performed to determine correlations between molecular and clinical/pathological patient data. None of the tested variants were identified in most (66.15%) of cases. The observed frequencies among the total samples vs. only the adenocarcinoma cases were notable different, with the highest frequency being the KRAS mutation (24.49% vs. 35.55%), followed by EGFR (6.96% vs. 10.23%), PIK3CA (1.20% vs. 0.9%), BRAF (1.08% vs. 1.62%), ALK (0.12% vs. 0.18%), while the lowest was the HER2 mutation (0% for both). The statistical analysis yielded correlations between presence of a mutation with gender, cancer type, vascular invasion and smoking history. The outcome of this study will provide data that helps stratify patient prognosis and supports development of more precise treatments, resulting in improved outcomes for future lung cancer patients.


Assuntos
Adenocarcinoma/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Predisposição Genética para Doença , Prognóstico , Adenocarcinoma/classificação , Adenocarcinoma/epidemiologia , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Quinase do Linfoma Anaplásico/genética , Carcinoma Pulmonar de Células não Pequenas/classificação , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Classe I de Fosfatidilinositol 3-Quinases/genética , Receptores ErbB/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Receptor ErbB-2/genética
14.
PLoS One ; 15(8): e0237098, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32745124

RESUMO

The EGFR-targeting cancer therapies are commonly facing drug resistance, mostly due to mutations. Gene therapy with artificial microRNA targeting EGFR conserved sequence may avoid such problem. In this study, we constructed a recombinant adenovirus expressing EGFR-targeting artificial microRNA and active revCASP3 (Ad-EC), under the control of tumor-specific SLPI promoter, and evaluated its inhibitory effect on HEP-2 cancer cells both in vitro and in vivo. MTT assay showed that cell growth inhibition rate at 72h was 44.0% in Ad-EC group at MOI 50, while the rate was 7.7% in the control virus Ad-GFP group and 3.6% in Cetuximab (500 µg/ml) group respectively. Flow cytometry analysis revealed the late apoptotic cells rate was 36.1% in Ad-EC group, significantly higher than 6.5% of Ad-GFP group (p < 0.001). When Ad-EC (MOI 50) was combined with CDDP (0.25 µg/ml), late apoptotic cells rate increased to 61.2%, significantly higher than each monotherapy group (P < 0.001). The real-time xCELLigence system recorded an effective cell growth inhibition in Ad-EC and CDDP groups, and more enhanced effect in Ad-EC plus CDDP group. Western blot revealed that Ad-EC could inhibit the activation of AKT pathway and ERK1/2 pathway, while Cetuximab had the AKT pathway over-activated. In vivo experiments with HEP-2 xenograft in nude mice confirmed the tumor inhibition in Ad-EC, CDDP and Ad-EC plus CDDP groups compared with PBS group (P < 0.01). Collectively, these data support the effective inhibition of cancer cells by this novel gene therapy strategy.


Assuntos
Caspase 3/metabolismo , Receptores ErbB/genética , MicroRNAs/genética , Neoplasias Experimentais/terapia , Terapêutica com RNAi/métodos , Adenoviridae/genética , Animais , Protocolos de Quimioterapia Combinada Antineoplásica , Apoptose , Caspase 3/genética , Linhagem Celular Tumoral , Proliferação de Células , Cetuximab/administração & dosagem , Cetuximab/uso terapêutico , Cisplatino/administração & dosagem , Cisplatino/uso terapêutico , Receptores ErbB/metabolismo , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Neoplasias Experimentais/tratamento farmacológico , Proteínas Proto-Oncogênicas c-akt/metabolismo
16.
J Cancer Res Clin Oncol ; 146(11): 2851-2859, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32743759

RESUMO

PURPOSE: TP53/EGFR co-mutation has been reported to affect the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in lung adenocarcinoma (LUAD). However, its impact on survival is unclear. In this analysis, we explored the prognostic effect of TP53/EGFR co-mutation in LUAD. METHODS: Clinical data and transcriptome sequencing of LUAD patients with matched genomic data were downloaded from the Cancer Genome Atlas (TCGA) database for overall survival (OS) analysis. Differential expression genes (DEGs) were recognized by R software and bioconductor package. Clusterprofiler was used for functional analysis. STRING was used for estimating PPI information and plug-in CytoHubba to screen hub modules in Cytoscape. The association between tumor mutation burden (TMB) and survival was also analyzed. RESULTS: OS was shorter for patients carrying TP53 mutation (MUT) than that of wild type (WT) (37.7 m vs 52.8 m; p = 0.040, HR = 1.38, 95% CI 1.01-1.89). Dual TP53/EGFR-MUT was associated with inferior OS compared with the dual WT/WT cohort (38.4 m vs 51.9 m; p = 0.023, HR 1.83, 95% CI 0.95-3.52). 316 DEGs between dual TP53/EGFR-MUT and dual WT/WT samples were obtained and functional analysis made known that DEGs were strikingly enriched in regulating the metabolism of important amino acids, cell division, cell cycle regulation, cell adhesion, and extracellular matrix composition. KEGG analysis discovered that DEGs were mainly enriched in signaling pathways such as PI3K-Akt, cytokine-cytokine receptor interaction, focal adhesions, and extracellular matrix receptor interaction. PPI network suggested that GPC3, CCL28, GPR37, and NPY genes were up-regulated in dual mutation samples. OS in the high TMB cohort was significantly better than that in the low TMB in patients with TP53 MUT(43.2 m vs 32.4 m; P = 0.007, HR = 0.52, 95% CI: 0.34-0.81), as well as in the combination of TP53 MUT and EGFR WT group (44.4 m vs 31.2 m; P = 0.021, HR = 0.55, 95% CI 0.34 - 0.89). CONCLUSIONS: TP53 MUT is a poor prognostic factor in LUAD patients, and the prognosis of TP53/EGFR co-mutation is worse. GPC3, CCL28, GPR37, and NPY may be novel prognostic markers and potential therapeutic targets for patients with dual TP53/EGFR mutation LUAD.


Assuntos
Adenocarcinoma de Pulmão/genética , Neoplasias Pulmonares/genética , Proteína Supressora de Tumor p53/genética , Adenocarcinoma de Pulmão/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Receptores ErbB/genética , Feminino , Genes erbB-1 , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida
17.
Anticancer Res ; 40(8): 4401-4404, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32727769

RESUMO

BACKGROUND: The occurrence of lung adenocarcinoma metastasizing to the pancreas is overall rare and can histologically imitate primary pancreatic ductal carcinoma (PDAC). CASE REPORT: This is a case report of a 70-year-old female with a history of surgically resected right lung adenocarcinoma presenting for routine follow up without symptoms. CT scans revealed a pancreatic cystic mass with ductal dilatation that was sampled via endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) and thought to be a primary pancreatic mucinous neoplasm with high grade dysplasia suspicious for carcinoma based on smear cytology. On repeat EUS-FNA and biopsy (FNB) with additional immunohistochemical testing for lung adenocarcinoma markers thyroid transcription factor (TTF1) and Napsin A and molecular testing, the lesion was identified as a metastasis of lung adenocarcinoma with an epidermal growth factor receptor (EGFR L858R) mutation; subsequently, the patient underwent targeted therapy that yielded an almost complete response. CONCLUSION: To the best of our knowledge, this is the first documented case in English literature of a lung adenocarcinoma metastasis to the pancreas mimicking a pancreatic primary neoplasm and highlights the potential pitfalls of EUS-FNA for the diagnosis of certain metastases to the pancreas.


Assuntos
Adenocarcinoma de Pulmão/diagnóstico por imagem , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pancreáticas/secundário , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Idoso , Biomarcadores/metabolismo , Carcinoma Ductal Pancreático/diagnóstico por imagem , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Diagnóstico Diferencial , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Mutação , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Tomografia Computadorizada por Raios X
18.
Medicine (Baltimore) ; 99(29): e21275, 2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-32702917

RESUMO

This observational study evaluated the treatment outcomes of clinical factors on the patients with lung adenocarcinoma with epidermal growth factor receptor mutations who received tyrosine kinase inhibitors as first-line treatment.Patients with stage IIIb or IV lung adenocarcinoma with mutated epidermal growth factor receptor were enrolled retrospectively between March 2010 and December 2017. The hematologic markers on progression-free survival (PFS) and overall survival (OS) were analyzed.Totally 190 patients were enrolled. In univariate analysis by hematologic markers, lower lymphocyte percentage and higher platelet count were associated with significantly poor PFS and OS. Multivariate analysis showed lower lymphocyte percentage was independent poor prognostic factors for PFS and OS. Higher platelet count was an independent poor prognostic factor for OS only.Patients with lung adenocarcinoma receiving tyrosine kinase inhibitors with lower lymphocyte percentage and higher platelet count had poorer prognoses compared with other patients.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Antineoplásicos/uso terapêutico , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Contagem de Linfócitos , Contagem de Plaquetas , Proteínas Tirosina Quinases/antagonistas & inibidores , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Resultado do Tratamento
19.
PLoS One ; 15(7): e0234818, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32663210

RESUMO

BACKGROUND: Erlotinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors used to treat EGFR mutation positive non-small-cell lung cancer (NSCLC). Skin rash and diarrhea are well-known and common adverse events in patients receiving erlotinib, whereas other adverse events, including eye, liver, or renal disorders have not been evaluated adequately. This meta-analysis aimed to evaluate the ocular, hepatobiliary, and renal toxicities of erlotinib in patients with NSCLC cancers. METHODS: In total, sixty studies were assessed, and the results of the included studies were quantitatively integrated using meta-analysis. The incidence of ocular, hepatobiliary (alanine aminotransferase [ALT] and bilirubin elevations; other hepatic adverse events), and renal adverse events were estimated. Additionally, the erlotinib-treated groups and the control groups (placebo or other treatment) were compared with respect to ocular disorders and ALT elevation. The study protocol has been registered in the International Prospective Register for Systematic Reviews (PROSPERO) CRD42018093758. RESULTS: The overall incidence of ocular disorders was 3.30% (95% confidence interval [CI] 2.20%-5.00%). The incidence of ALT elevation, bilirubin elevation, and other hepatobiliary disorders was 6.40% (95% CI 3.90%-10.4%), 3.80% (95% CI 2.30%-6.10%), and 1.00% (95% 0.60%-1.80%), respectively. The incidence of renal disorder was 3.10% (95% CI 1.90%-5.00%). The risk of ocular toxicity in the erlotinib treatment group was significantly increased (risk ratio = 2.91; 95% CI 1.70-4.98) compared to that in the control group. ALT elevation was not significantly different between the two groups. CONCLUSION: Based on the results, careful monitoring of ocular toxicity in patients receiving erlotinib should be recommended and closer monitoring of hepatic toxicity should be also recommended in patients with liver-related risk factors.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/fisiopatologia , Cloridrato de Erlotinib/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doenças do Sistema Digestório/etiologia , Intervalo Livre de Doença , Receptores ErbB/genética , Cloridrato de Erlotinib/uso terapêutico , Exantema/etiologia , Olho/efeitos dos fármacos , Oftalmopatias/etiologia , Feminino , Trato Gastrointestinal/efeitos dos fármacos , Humanos , Rim/efeitos dos fármacos , Nefropatias/etiologia , Neoplasias Pulmonares/genética , Masculino , Mutação , Inibidores de Proteínas Quinases/uso terapêutico
20.
Nat Commun ; 11(1): 3660, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32694521

RESUMO

High expression or aberrant activation of epidermal growth factor receptor (EGFR) is related to tumor progression and therapy resistance across cancer types, including non-small cell lung cancer (NSCLC). EGFR tyrosine kinase inhibitors (TKIs) are first-line therapy for NSCLC. However, patients eventually deteriorate after inevitable acquisition of EGFR TKI-resistant mutations, highlighting the need for therapeutics with alternative mechanisms of action. Here, we report that the elevated tribbles pseudokinase 3 (TRIB3) is positively associated with EGFR stability and NSCLC progression. TRIB3 interacts with EGFR and recruits PKCα to induce a Thr654 phosphorylation and WWP1-induced Lys689 ubiquitination in the EGFR juxtamembrane region, which enhances EGFR recycling, stability, downstream activity, and NSCLC stemness. Disturbing the TRIB3-EGFR interaction with a stapled peptide attenuates NSCLC progression by accelerating EGFR degradation and sensitizes NSCLC cells to chemotherapeutic agents. These findings indicate that targeting EGFR degradation is a previously unappreciated therapeutic option in EGFR-related NSCLC.


Assuntos
Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Proteínas de Ciclo Celular/metabolismo , Neoplasias Pulmonares/patologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Proteínas Repressoras/metabolismo , Adulto , Animais , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Linhagem Celular Tumoral , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidade , Masculino , Camundongos , Pessoa de Meia-Idade , Mutação , Fosforilação/efeitos dos fármacos , Proteína Quinase C-alfa/metabolismo , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Estabilidade Proteica/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Proteólise/efeitos dos fármacos , Taxa de Sobrevida , Ubiquitinação/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
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