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1.
Medicine (Baltimore) ; 100(26): e26449, 2021 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-34190169

RESUMO

RATIONALE: Anaplastic lymphoma kinase (ALK) inhibitors have been approved for patients with ALK-rearrangement lung cancer. The effect is superior to the standard first-line therapy of pemetrexed plus platinum-based chemotherapy. However, ALK inhibitors are associated with rare and sometimes fatal adverse events. Organizing pneumonitis (OP) is a rare and serious adverse event usually caused by ceritinib, and it is easily misdiagnosed as infectious pneumonia, metastasis, or cancer progression. PATIENT CONCERNS: A 56-year-old female presented with chest tightness and dyspnea for more than 10 days. She was previously healthy with no significant medical history. Workup including chest computed tomography (CT), pathological examination of a biopsy specimen, and next-generation sequencing was consistent with a diagnosis of IVA ALK-rearrangement lung adenocarcinoma. She was treated with pemetrexed plus platinum-based chemotherapy and crizotinib concurrently, followed by maintenance therapy with crizotinib alone and she had an almost complete response. However, about 26 months after beginning treatment she developed multiple brain metastases. Crizotinib was discontinued and she was begun on ceritinib. After about 3 months the brain metastases had almost complete response. After 5 months of ceritinib, however, multiple patchy lesions appeared in the bilateral upper lungs. DIAGNOSES: Treatment with antibiotics had no effect and blood and sputum cultures are negative. A CT-guided biopsy of the upper lung was performed, and pathological hematoxylin-eosin staining and immunohistochemical studies were consistent with OP. INTERVENTIONS: Ceritinib was discontinued, she was begun on prednisone 0.5 mg/kg orally every day, and regular follow-up is necessary. OUTCOMES: CT of the chest 2 and 4 weeks after beginning prednisone showed the lung lesions to be gradually resolving, and she was continued on prednisone for 2 months and gradually reduced the dose of prednisone every 2 weeks. No related adverse events were occurred in patient. LESSONS: OP must be differentiated from infectious pneumonia, metastasis, or cancer progression. The mechanism of OP is still unknown and needs further research. Biopsy plays a role in making a diagnosis of OP. In our patient, discontinuing ceritinib and treating her with prednisone resulted in a good outcome.


Assuntos
Adenocarcinoma de Pulmão , Quinase do Linfoma Anaplásico , Pneumonia em Organização Criptogênica , Neoplasias Pulmonares , Prednisona/administração & dosagem , Pirimidinas , Sulfonas , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Adenocarcinoma de Pulmão/fisiopatologia , Quinase do Linfoma Anaplásico/antagonistas & inibidores , Quinase do Linfoma Anaplásico/genética , Antineoplásicos/uso terapêutico , Biópsia/métodos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Crizotinibe/uso terapêutico , Pneumonia em Organização Criptogênica/induzido quimicamente , Pneumonia em Organização Criptogênica/patologia , Pneumonia em Organização Criptogênica/terapia , Substituição de Medicamentos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Pulmão/diagnóstico por imagem , Pulmão/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/fisiopatologia , Pessoa de Meia-Idade , Pemetrexede/uso terapêutico , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Sulfonas/administração & dosagem , Sulfonas/efeitos adversos , Tomografia Computadorizada por Raios X/métodos , Resultado do Tratamento
2.
Gan To Kagaku Ryoho ; 48(6): 845-847, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34139737

RESUMO

A 57-year-old female was diagnosed as having advanced lung adenocarcinoma. Combination chemotherapy using cisplatin plus pemetrexed was introduced. However, her disease progressed during the maintenance therapy with pemetrexed. Subsequent therapies could not control the disease. Later, it was found that her lung cancer harbored an epidermal growth factor receptor(EGFR)exon 20 insertion, D770_N771insSVD. Afatinib, a second-generation EGFR-tyrosine kinase inhibitor (TKI), was administered as the fourth-line treatment and reduced the size in several lesions. Although EGFR-TKIs are generally not recommended as the first-line treatment for lung cancers with EGFR exon 20 insertions, afatinib could be a useful therapeutic option in the second-line or later therapy for this type of exon 20 insertion, D770_N771insSVD.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Receptores ErbB/genética , Éxons , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Pessoa de Meia-Idade , Mutação , Inibidores de Proteínas Quinases/uso terapêutico
3.
Magy Onkol ; 65(2): 103-111, 2021 Jun 03.
Artigo em Húngaro | MEDLINE | ID: mdl-34081758

RESUMO

The therapeutic impact of KRAS mutations remains controversial in bone metastatic lung adenocarcinoma (LADC). Therefore, our aim was to investigate the effects of KRAS mutational status on overall survival (OS) in these patients according to bisphosphonate therapy (BTx) and radiation therapy (RTx). In total, 134 LADC patients diagnosed with simultaneous bone metastasis were included in this study. The results of the univariate (p=0.008) and multivariate (p=0.004) survival analyses indicated that KRAS mutation is a negative prognostic factor. Both BTx and RTx can increase the OS with a pronounced benefit for patients with KRAS wild-type tumors. Importantly, the concomitant use of BTx and RTx might increase the OS irrespective of KRAS status compared to BTx or RTx alone. In summary, our results might contribute to the development of new therapeutic approaches with regards to KRAS mutational status in bone metastatic LADC.


Assuntos
Adenocarcinoma de Pulmão , Adenocarcinoma , Neoplasias Colorretais , Neoplasias Pulmonares , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Difosfonatos/uso terapêutico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Prognóstico , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas ras/genética
4.
Cancer Med ; 10(10): 3323-3331, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33932095

RESUMO

BACKGROUND: Sputum cell-free DNA (cfDNA) is a valuable surrogate sample for assessing EGFR-sensitizing mutations in patients with advanced lung adenocarcinoma. Detecting EGFR exon 20 p.T790 M (p.T790 M) is much more challenging due to its limited availability in tumor tissues. Exploring sputum cfDNA as an alternative for liquid-based sample type in detecting p.T790 M requires potential improvement in clinical practice. METHODS: A total of 34 patients with EGFR-sensitive mutation-positive lung adenocarcinoma and acquired resistance to the first generation of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) were enrolled. The sputum samples, and paired tumors and/or plasma samples were tested for p.T790 M mutation and concordance of p.T790 M status among the three sample types was analyzed. RESULTS: The overall concordance rate of p.T790 M mutation between sputum cfDNA and tumor tissue samples was 85.7%, with a sensitivity of 66.7% and a specificity of 100%. The sensitivity for detecting p.T790 M in sputum cfDNA was 100%, 66.7%, and 0% in the three sputum groups of malignant, satisfactory but no malignant cells, and unsatisfactory, respectively. The combined results of plasma cfDNA testing and sputum cfDNA testing further increased the sensitivity to 100% for p.T790 M detection in satisfactory but no malignant cells sputum group. CONCLUSION: These findings revealed that cfDNA from malignant or satisfied but no malignant cells sputum is considered suitable for detecting p.T790 M mutation in patients with acquired resistance to first or second-generation EGFR-TKIs. The sputum cytological pathological evaluation-guided sputum cfDNA testing assists in significantly improving the sensitivity of p.T790 M detection, bringing significant value for the maximal application of third-generation EGFR-TKIs in second-line treatment.


Assuntos
Adenocarcinoma de Pulmão/genética , Ácidos Nucleicos Livres/genética , Resistencia a Medicamentos Antineoplásicos/genética , Éxons/genética , Neoplasias Pulmonares/genética , Mutação/genética , Adenocarcinoma de Pulmão/tratamento farmacológico , Idoso , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/uso terapêutico , Escarro
5.
BMJ Case Rep ; 14(5)2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34039541

RESUMO

A 39-year-old female Chinese non-smoker was diagnosed with epidermal growth factor receptor mutation-positive lung adenocarcinoma with cerebral metastases and commenced erlotinib. After 5 weeks, she presented with a 3-day history of severe bilateral facial weakness (House-Brackmann grade V/VI) and hypogeusia consistent with bilateral facial nerve palsies. MRI demonstrated new, symmetrical contrast-enhancing foci at the expected location of the facial nerves, consistent with leptomeningeal progression. Erlotinib was ceased and osimertinib was commenced. Facial nerve motor and sensory function began to improve within 1 week and by 2 weeks had returned to near normal. Review at 2 and 6 months demonstrated normal facial nerve function and progressive resolution of the facial nerve lesions on MRI. While rare, leptomeningeal malignancy may present as simultaneous bilateral facial nerve palsies. Osimertinib has superior central nervous system penetration and in this case was associated with rapid and sustained clinical and radiographical resolution of the facial nerve lesions.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Acrilamidas , Adenocarcinoma de Pulmão/diagnóstico por imagem , Adenocarcinoma de Pulmão/tratamento farmacológico , Adulto , Compostos de Anilina , Nervo Facial , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/tratamento farmacológico
6.
J Int Med Res ; 49(4): 3000605211004021, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33794676

RESUMO

OBJECTIVE: This study aimed to identify a predictive marker of response to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in patients with EGFR-mutant advanced lung adenocarcinoma. METHODS: A cohort of 190 patients with EGFR-mutant advanced lung adenocarcinoma was analyzed. Receiver operating characteristic curve analysis was used to evaluate the optimal cutoffs for fibrinogen levels, the neutrophil-to-lymphocyte ratio (NLR), and the platelet-to-lymphocyte ratio (PLR) for predicting progression-free survival (PFS). Univariate and multivariate survival analyses were performed to identify factors correlated with PFS and overall survival (OS). RESULTS: High NLR was associated with worse performance status. In univariate analysis, fibrinogen levels, NLR, and PLR were correlated with OS and PFS. In multivariate analysis, all three variables remained predictive of OS, whereas only fibrinogen levels and PLR were independent prognostic factors for PFS. Furthermore, the combination of fibrinogen levels and PLR (F-PLR score) could stratify patients into three groups with significantly different prognoses, and the score was independently predictive of survival. CONCLUSION: The F-PLR score predicted the prognosis of patients with EGFR-mutant advanced lung adenocarcinoma who received EGFR-TKIs, and this score may serve as a convenient blood-based marker for identifying high-risk patients.


Assuntos
Adenocarcinoma de Pulmão , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Receptores ErbB/genética , Fibrinogênio , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Linfócitos , Neutrófilos , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Estudos Retrospectivos
7.
Int J Mol Sci ; 22(5)2021 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-33802597

RESUMO

Heat shock protein 90 (HSP90) plays an essential role in lung adenocarcinoma, acting as a key chaperone involved in the correct functioning of numerous highly relevant protein drivers of this disease. To this end, HSP90 inhibitors have emerged as promising therapeutic strategies, even though responses to them have been limited to date. Given the need to maximize treatment efficacy, the objective of this study was to use isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomic techniques to identify proteins in human lung adenocarcinoma cell lines whose basal abundances were correlated with response to HSP90 inhibitors (geldanamycin and radicicol derivatives). From the protein profiles identified according to response, the relationship between lactate dehydrogenase B (LDHB) and DNA topoisomerase 1 (TOP1) with respect to sensitivity and resistance, respectively, to geldanamycin derivatives is noteworthy. Likewise, rhotekin (RTKN) and decaprenyl diphosphate synthase subunit 2 (PDSS2) were correlated with sensitivity and resistance to radicicol derivatives. We also identified a relationship between resistance to HSP90 inhibition and the p53 pathway by glucose deprivation. In contrast, arginine biosynthesis was correlated with sensitivity to HSP90 inhibitors. Further study of these outcomes could enable the development of strategies to improve the clinical efficacy of HSP90 inhibition in patients with lung adenocarcinoma.


Assuntos
Adenocarcinoma de Pulmão/metabolismo , Biomarcadores Tumorais/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Neoplasias Pulmonares/metabolismo , Células A549 , Adenocarcinoma de Pulmão/tratamento farmacológico , Antineoplásicos/farmacologia , Benzoquinonas/farmacologia , Linhagem Celular Tumoral , Humanos , Lactamas Macrocíclicas/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Chaperonas Moleculares/metabolismo , Proteômica/métodos
8.
BMJ Case Rep ; 14(4)2021 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-33906872

RESUMO

This report concerns a patient with skeletal muscle metastases due to lung adenocarcinoma harbouring an echinoderm microtubule-associated protein-like-4 (EML4)-anaplastic lymphoma kinase (ALK) rearrangement, who was successfully treated with lorlatinib after resistance to alectinib. A right lower lobectomy based on a diagnosis of lung adenocarcinoma was performed on a 77-year-old Japanese woman. After 7 months of surgical resection, a mass in the right calf was observed. A fine-needle aspiration biopsy from the mass was performed and the mass was diagnosed as metastatic adenocarcinoma harbouring EML4-ALK rearrangement. Alectinib was administered for 10 months. Then, administration of lorlatinib, an ALK tyrosine kinase inhibitor classified as third generation, was initiated after resistance to treatment with alectinib. After starting treatment with lorlatinib, the gastrocnemius tumour diminished and has maintained a stable condition. Our case suggests that EML4-ALK positive lung adenocarcinoma is treatable with lorlatinib after resistance to treatment with alectinib.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Idoso , Carbazóis , Feminino , Humanos , Lactamas Macrocíclicas , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Músculo Esquelético , Proteínas de Fusão Oncogênica/genética , Piperidinas , Inibidores de Proteínas Quinases/uso terapêutico
9.
J Int Med Res ; 49(4): 300060521996868, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33926295

RESUMO

Immunoglobulin A nephropathy (lgAN) is a common primary glomerulonephritis, but paraneoplastic IgAN has been rarely reported. This current case report describes a 49-year-old male patient that was referred with proteinuria, oedema and hypoproteinaemia after lung cancer surgery and before the first cycle of chemotherapy. Renal biopsy confirmed lgAN. The patient received four cycles of chemotherapy (first cycle: pemetrexed + nedaplatin; second to fourth cycle: pemetrexed + carboplatin). The symptoms of IgAN were gradually relieved with additional cycles of chemotherapy. At the latest follow-up on 10 February 2020, there was no evidence of lung cancer recurrence and all symptoms of lgAN had disappeared. lgAN combined with lung adenocarcinoma is quite rare, which suggests that IgAN might be a paraneoplastic manifestation of lung adenocarcinoma.


Assuntos
Adenocarcinoma de Pulmão , Glomerulonefrite por IGA , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/complicações , Adenocarcinoma de Pulmão/diagnóstico por imagem , Adenocarcinoma de Pulmão/tratamento farmacológico , Glomerulonefrite por IGA/complicações , Glomerulonefrite por IGA/tratamento farmacológico , Humanos , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Proteinúria
10.
Mol Biol Rep ; 48(4): 3813-3825, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33856604

RESUMO

Lung cancer is the leading cancer type of death rate. The lung adenocarcinoma subtype is responsible for almost half of the total lung cancer deaths. Despite the improvements in cancer treatment in recent years, lung adenocarcinoma patients' overall survival rate remains poor. Immunetherapy and chemotherapy are two of the most widely used options for the treatment of cancer. Although many cancer types initially respond to these treatments, the development of resistance is inevitable. The rapid development of drug resistance mainly characterizes lung adenocarcinoma. Despite being the subject of many studies in recent years, the resistance initiation and progression mechanism is still unclear. In this review, we have examined the role of the primary DNA repair pathways (non-homologous end joining (NHEJ) pathway, homologous-recombinant repair (HR) pathway, base excision repair (BER) pathway, and nucleotide excision repair (NER) pathway and transactivation mechanisms of tumor protein 53 (TP53) in drug resistance development. This review suggests that mentioned pathways have essential roles in developing the resistance against chemotherapy and immunotherapy in lung adenocarcinoma patients.


Assuntos
Adenocarcinoma de Pulmão/genética , Reparo do DNA , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/genética , Adenocarcinoma de Pulmão/tratamento farmacológico , Animais , Humanos , Neoplasias Pulmonares/tratamento farmacológico
11.
J Cancer Res Clin Oncol ; 147(7): 2079-2092, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33797608

RESUMO

AIM: This study is designed to ascertain the relative molecular targets of effective Chinese herbs in treating stage IV lung adenocarcinoma based on clinical data and network pharmacology. In addition, we showed that Chinese Herbal Medicine (CHM) treatment was associated with survival benefit for patients with stage IV lung adenocarcinoma and identified 18 herbs beneficial to survival through correlation analysis. BACKGROUND: Increasing evidence has shown that CHM has efficient therapeutic effects for advanced lung adenocarcinoma, while active ingredients and potential targets remain unclear. METHODS: Kaplan-Meier method and Cox regression analysis were used to evaluate the survival benefit of CHM treatment, and correlation analysis was applied to identify the most effective components in the formulas. A network pharmacological approach was used to decipher the potential therapeutic mechanisms of CHM. RESULTS: CHM treatment was an independent protective factor. The hazard ratio (HR) was 0.487 (95% CI 0.293-0.807; P = 0.005). Patients in the CHM group had a longer median survival time (31 months) compared with the non-CHM group (19 months; P < 0.001). 18 out of the total 241 herbs were significantly correlated with favorable survival outcomes (P < 0.05), likely representing the most effective components in these formulas. Bioinformatics analysis suggested that the 18 herbs realize anti-lung-adenocarcinoma activity mainly through (1) inhibiting the activity of some growth factors' receptors, such as HGFR, EGFR, and IGFR. (2) Suppressing angiogenesis not only through VEGFR and PDGFR, but also through the function of neurotransmitters such as dopamine and serotonin. (3) Inhibiting the Ras signaling pathway directly through Ras as well as through ALK and FNTA/FNTB. CONCLUSIONS: We performed a network pharmacological method to decipher the underlying mechanisms, which provides a good foundation for herbal research based on clinical data.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Biomarcadores Tumorais/metabolismo , Medicamentos de Ervas Chinesas/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/farmacologia , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Idoso , Biomarcadores Tumorais/genética , Bases de Dados de Produtos Farmacêuticos , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Masculino , Simulação de Acoplamento Molecular , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
12.
Int J Mol Sci ; 22(8)2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33924522

RESUMO

(1) Background: Acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is an intractable problem for many clinical oncologists. The mechanisms of resistance to EGFR-TKIs are complex. Long non-coding RNAs (lncRNAs) may play an important role in cancer development and metastasis. However, the biological process between lncRNAs and drug resistance to EGFR-mutated lung cancer remains largely unknown. (2) Methods: Osimertinib- and afatinib-resistant EGFR-mutated lung cancer cells were established using a stepwise method. A microarray analysis of non-coding and coding RNAs was performed using parental and resistant EGFR-mutant non-small cell lung cancer (NSCLC) cells and evaluated by bioinformatics analysis through medical-industrial collaboration. (3) Results: Colorectal neoplasia differentially expressed (CRNDE) and DiGeorge syndrome critical region gene 5 (DGCR5) lncRNAs were highly expressed in EGFR-TKI-resistant cells by microarray analysis. RNA-protein binding analysis revealed eukaryotic translation initiation factor 4A3 (eIF4A3) bound in an overlapping manner to CRNDE and DGCR5. The CRNDE downregulates the expression of eIF4A3, mucin 1 (MUC1), and phospho-EGFR. Inhibition of CRNDE activated the eIF4A3/MUC1/EGFR signaling pathway and apoptotic activity, and restored sensitivity to EGFR-TKIs. (4) Conclusions: The results showed that CRNDE is associated with the development of resistance to EGFR-TKIs. CRNDE may be a novel therapeutic target to conquer EGFR-mutant NSCLC.


Assuntos
RNA Helicases DEAD-box/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/genética , Fator de Iniciação 4A em Eucariotos/metabolismo , Neoplasias Pulmonares/genética , Mucina-1/metabolismo , Mutação/genética , Inibidores de Proteínas Quinases/farmacologia , RNA Longo não Codificante/metabolismo , Acrilamidas/farmacologia , Acrilamidas/uso terapêutico , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Compostos de Anilina/farmacologia , Compostos de Anilina/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/genética , 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 , Neoplasias Colorretais/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Concentração Inibidora 50 , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Modelos Biológicos , Inibidores de Proteínas Quinases/uso terapêutico , RNA Longo não Codificante/genética , Transdução de Sinais/efeitos dos fármacos
13.
Jpn J Clin Oncol ; 51(6): 956-965, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-33829270

RESUMO

OBJECTIVE: A third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), osimertinib, is the standard treatment for patients with non-small cell lung cancer harbouring mutant EGFR. Unfortunately, these patients inevitably acquire resistance to EGFR-TKI therapies, including osimertinib. However, the mechanism associated with this resistance remains unclear. METHODS: A 63-year-old Japanese female with lung adenocarcinoma underwent right upper lobectomy (pT1bN2M0 pStage IIIA, EGFR Ex21 L858R). She manifested post-operative tumour recurrence with multiple lung metastases 8 months later and began gefitinib treatment. The lung lesions re-grew 15 months later, and EGFR T790M mutation was detected in the lung metastasis re-biopsy. She was administered osimertinib; however, it relapsed with pleural effusion 16 months later. We isolated cells from the osimertinib-resistant pleural effusion to establish a novel cell line, ABC-31. RESULTS: Although the EGFR L858R mutation was detected in ABC-31 cells, the T790M mutation was lost. ABC-31 cells were resistant to EGFR-TKIs, including osimertinib. Phospho-receptor tyrosine kinase array revealed activation of the insulin-like growth factor 1 receptor (IGF1R), whereas overexpression of the IGF1R ligand, IGF2, induced IGF1R activation in ABC-31 cells. Combination therapy using EGFR-TKIs and IGF1R inhibitor acted synergistically in vitro. She was re-administered osimertinib since EGFR-TKIs and IGF1R inhibitor combination therapy was impossible in clinical practice. This had a slight and short-lived effect. CONCLUSIONS: Taken together, we have successfully established a new osimertinib-resistant lung adenocarcinoma cell line with activated IGF1R. These ABC-31 cells will help develop novel therapeutic strategies for patients with lung adenocarcinoma resistant to specific treatment via IGF1R activation.


Assuntos
Acrilamidas/farmacologia , Adenocarcinoma de Pulmão/genética , Compostos de Anilina/farmacologia , Neoplasias Pulmonares/genética , Receptor IGF Tipo 1/metabolismo , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , 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/patologia , Linhagem Celular Tumoral , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Pessoa de Meia-Idade , Mutação , Inibidores de Proteínas Quinases/farmacologia
15.
BMC Womens Health ; 21(1): 152, 2021 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-33853580

RESUMO

BACKGROUND: Lung adenocarcinoma which invades ovaries is very rare. However, with the increase of long-survival female lung cancer, more patients will suffer ovarian metastasis. On grounds of the paucity of reported cases, the clinicopathological features and treatment strategies remain unknown. CASE PRESENTATION: This patient was stage IV lung adenocarcinoma at first diagnosis. Following multiple-line systemic treatments, she experienced extensive pelvic metastasis. After debulking surgery and reevaluation about the drive genes, she was administered by targeted therapy. Up to now, the patient has shown no evidence of progression for 8 years after the initial diagnosis of primary lung cancer and 46 months after her ovarian metastasis. CONCLUSION: The comprehensive treatment modality for the bilateral ovarian metastasis is effective in clinical course.


Assuntos
Adenocarcinoma de Pulmão , Adenocarcinoma , Neoplasias Pulmonares , Neoplasias Ovarianas , Adenocarcinoma de Pulmão/tratamento farmacológico , Feminino , Humanos , Neoplasias Pulmonares/tratamento farmacológico
16.
Lung Cancer ; 156: 1-4, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33845248

RESUMO

OBJECTIVES: Pembrolizumab is a standard treatment for non-small cell lung cancer (NSCLC) with high-PD-L1 expression; however, its effect is dismal in patients with poor physical condition. Additionally, the effect of immunotherapy is generally limited in NSCLC harboring driver mutations such asEGFR, ALK, or RET gene aberrations. RESULTS: We report the beneficial effect of pembrolizumab in a patient with poor performance status and PD-L1+ lung adenocarcinoma with theCCDC6-RET fusion gene and co-occurring NF1/TP53 mutations, complicated by multiple cancer-associated thrombi and respiratory failure. CONCLUSIONS: Further studies are warranted to establish the role of co-occurring NF1/TP53 mutations as a positive predictive biomarker for pembrolizumab in NSCLC harboring RET fusion genes.


Assuntos
Adenocarcinoma de Pulmão , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Trombose , Adenocarcinoma de Pulmão/complicações , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Anticorpos Monoclonais Humanizados , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Proteínas do Citoesqueleto , Humanos , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Proteínas Proto-Oncogênicas c-ret/genética , Proteína Supressora de Tumor p53/genética
17.
Free Radic Biol Med ; 168: 25-43, 2021 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-33785413

RESUMO

The m6A reader YT521-B homology containing 2 (YTHDC2) has been identified to inhibit lung adenocarcinoma (LUAD) tumorigenesis by suppressing solute carrier 7A11 (SLC7A11)-dependent antioxidant function. SLC7A11 is a major functional subunit of system XC-. Inhibition of system XC- can induce ferroptosis. However, whether suppressing SLC7A11 is sufficient for YTHDC2 to be an endogenous ferroptosis inducer in LUAD is unknown. Here, we found that induction of YTHDC2 to a high level can induce ferroptosis in LUAD cells but not in lung and bronchus epithelial cells. In addition to SLC7A11, solute carrier 3A2 (SLC3A2), another subunit of system XC- was equally important for YTHDC2-induced ferroptosis. YTHDC2 m6A-dependently destabilized Homeo box A13 (HOXA13) mRNA because a potential m6A recognition site was identified within its 3' untranslated region (3'UTR). Interestingly, HOXA13 acted as a transcription factor to stimulate SLC3A2 expression. Thereby, YTHDC2 suppressed SLC3A2 via inhibiting HOXA13 in an m6A-indirect manner. Mouse experiments further confirmed the associations among YTHDC2, SLC3A2 and HOXA13, and demonstrated that SLC3A2 and SLC7A11 were both important for YTHDC2-impaired tumor growth and -induced lipid peroxidation in vivo. Moreover, higher expression of SLC7A11, SLC3A2 and HOXA13 indicate poorer clinical outcome in YTHDC2-suppressed LUAD patients. In conclusion, YTHDC2 is believed to be a powerful endogenous ferroptosis inducer and targeting SLC3A2 subunit of system XC- is essential for this process. Increasing YTHDC2 is an alternative ferroptosis-based therapy to treat LUAD.


Assuntos
Adenocarcinoma de Pulmão , Ferroptose , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Sistema y+ de Transporte de Aminoácidos/genética , Animais , Carcinogênese , Cadeia Pesada da Proteína-1 Reguladora de Fusão , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Camundongos , RNA Helicases
19.
Lung Cancer ; 155: 20-27, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33714778

RESUMO

BACKGROUND: Transformation to small cell lung cancer (SCLC) is a resistance mechanism to tyrosine kinase inhibitor (TKI) treatment that develops in lung adenocarcinoma. The genomic and treatment outcomes in these populations have not been comprehensively reported in China. METHODS: We performed a retrospective study analyzing patients with advanced non-SCLC (NSCLC) from eight sites who were diagnosed with SCLC transformation after receiving epidermal growth factor receptor (EGFR)-TKI treatment including first/second- or third-generation EGFR-TKIs. We assessed the genomic features and clinical prognosis in these patients with EGFR-mutated lung cancer. RESULTS: Thirty-two eligible patients with EGFR mutations were identified, 25 of whom had sufficient tumor tissues for detection of genes by next-generation sequencing. The median progression free survival (mPFS) for first/second-generation TKIs was 14.0 months. The most common mutations identified in samples with transformation to SCLC were in TP53 (17/25, 68.0 %), RB1 (9/25, 36.0 %), and PIK3CA (3/25, 12.0 %), and the incidence rates of RB1 and TP53 mutations were similar between patients receiving first/second-generation and third-generation TKI treatment. The estimated median time to SCLC transformation was 17.0 months. After SCLC transformation, platinum-etoposide was the most common treatment regimen, and the mPFS after platinum-etoposide treatment was 3.5 months. Anlotinib showed good efficacy in these patients (overall response rate, 66.7 %; mPFS, 6.2 months). The median overall survival after the initial diagnosis of metastatic lung cancer was 34.5 months, and patients with small cell transformation after third-generation TKI treatment had better prognosis than patients with transformation after first/second-generation treatment (49.4 months vs. 20.0 months, P = 0.013). CONCLUSION: We observed that TP53 and RB1 mutations were common in Chinese patients with SCLC transformation, regardless of whether first/second-generation or third-generation EGFR-TKI treatments were used. Earlier occurrence of small cell transformation after EGFR-TKI treatment was associated with poorer prognosis of patients. After the standard chemotherapy regimens for the management of primary SCLC, anlotinib may be a therapeutic option.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , China , Receptores ErbB/genética , Genômica , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Estudos Retrospectivos , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/genética
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