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1.
Artículo en Inglés | MEDLINE | ID: mdl-33799753

RESUMEN

The aim of the current study is to investigate potential associations among Long Noncoding RNA (LncRNA) H19 single nucleotide polymorphism (SNP) and epidermal growth factor receptor (EGFR) phenotypes on the clinicopathological characteristics of lung adenocarcinoma (LADC). Five loci of LncRNA H19 SNPs (rs217727, rs2107425, rs2839698, rs3024270, and rs3741219) were genotyped by using TaqMan allelic discrimination in 223 LADC patients with wild-type EGFR phenotype and 323 LADC individuals with EGFR mutations. After the statistical analyses, patients with the EGFR mutation were related to a higher distribution frequency of rs217727 SNP CT heterozygote (p = 0.030), and the female population with EGFR mutation demonstrated a higher distribution frequency of rs217727 SNP CT heterozygote (p < 0.001) and rs2107425 CT heterozygote (p = 0.002). In addition, the presence of LncRNA H19 SNP rs217727 T allele (CT + TT) in patients with EGFR wild-type was associated to higher tumor T status (stage III or IV, p = 0.037) and poorer cell differentiation status (poor differentiation, p = 0.012) compared to those EGFR wild-type individuals with LncRNA H19 SNP rs217727 CC allele. Besides, a prominently higher tumor T status was found in subjects with LncRNA H19 SNP rs2107425 T allele (CT + TT) (stage III or IV, p = 0.007) compared to EGFR wild-type LADC individuals with LncRNA CC allele in EGFR wild-type patients. Our findings suggest that the presence of LncRNA H19 SNP rs217727 is related to the EGFR mutation in LADC patients, and the LncRNA H19 SNP rs217727 and rs2107425 are associated with progressed tumor status for LADC patients with EGFR wild-type.


Asunto(s)
Adenocarcinoma del Pulmón , Neoplasias Pulmonares , ARN Largo no Codificante , Adenocarcinoma del Pulmón/genética , Estudios de Casos y Controles , Receptores ErbB/genética , Femenino , Predisposición Genética a la Enfermedad , Humanos , Neoplasias Pulmonares/genética , Fenotipo , Polimorfismo de Nucleótido Simple , ARN Largo no Codificante/genética
2.
Anticancer Res ; 41(4): 2059-2065, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33813414

RESUMEN

BACKGROUND/AIM: We investigated efficacy differences for afatinib versus gefitinib in non-small-cell lung cancer (NSCLC) according to epidermal growth factor receptor (EGFR) mutations. PATIENTS AND METHODS: We retrospectively analysed data for 343 patients with NSCLC with performance status 1 having EGFR mutations treated with gefitinib or afatinib. Overall response rate (ORR) was tested by Fisher's exact test. Overall (OS) and progression-free (PFS) survival were estimated by Kaplan-Meier method. RESULTS: ORR did not differ in any group or subgroup. Among all patients, we observed significantly longer PFS for those treated with afatinib vs. gefitinib (median 13.4 vs. 9.5 months, p=0.026), but only a nonsignificant trend was observed for OS. We showed nonsignificant trends of better PFS and OS using afatinib for exon 19 deletion and L858R subgroups. We observed no significant PFS differences for other EGFR mutations but a nonsignificant trend towards better OS for those treated with afatinib. CONCLUSION: Afatinib led to longer PFS for patients with common EGFR mutations but not for those with rare mutations.


Asunto(s)
Afatinib/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Gefitinib/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , República Checa/epidemiología , Progresión de la Enfermedad , Receptores ErbB/genética , Femenino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Mutación , Estudios Retrospectivos , Resultado del Tratamiento , Adulto Joven
3.
Zhen Ci Yan Jiu ; 46(3): 180-6, 2021 Mar 25.
Artículo en Chino | MEDLINE | ID: mdl-33798289

RESUMEN

OBJECTIVE: To observe the effect of electroacupuncture (EA) at "Zusanli"(ST36) on the expression of epidermal growth factor receptor (EGFR), tumor necrosis factor α(TNF-α) transfer growth factor α(TGF-α), interleukin-8(IL-8), p38 mitogen-activated protein kinases (p38MAPK), mucin-5AC (MUC5AC) and other related factors in chronic obstructive pulmonary disease (COPD) rats, so as to reveal its underlying mechanisms in improving COPD. METHODS: A total of thirty male SD rats were randomly divided into normal control, model and EA groups, with 10 rats in each group. The COPD model was replicated using a combined method of tracheal infusion of lipopolysaccharide (LPS) and forced smoke-inhaling. EA (1-3 mA, 4 Hz/20 Hz) was applied to bilateral ST36 for 30 min, once daily for two consecutive weeks. The lung ventilation activities including the forced vital capacity (FVC) and forced expiratory volume (FEV) at 0.1 and 0.3 s (FEV0.1, FEV0.3) were detected. Histopathological changes of the middle lobe and bronchus of the right lung were observed after H.E. staining. The contents of TGF-α, TNF-α and IL-8 in the serum, bronchoalveolar lavage fluid (BALF) and superior lobe of the right lung were assayed by using ELISA, and the expression levels of EGFR, p38MAPK and MUC5AC proteins (inferior lobe of the left lung) and mRNAs (inferior lobe of the right lung) detected using Western blot, immunohistochemistry (strept avidin-biotin complex, SABC method) and real-time quantitative PCR, respectively. RESULTS: Compared with the normal group, the FVC, FEV0.1, FEV0.3, FEV0.1/FVC and FEV0.3/FVC levels were significantly decreased (P<0.01), while the contents of TNF-α, TGF-α and IL-8 in the serum, BALF and lung tissues, expression levels of EGFR, p38MAPK and MUC5AC mRNAs and proteins, and the immunoactivity of EGFR, p38MAPK and MUC5AC in the lung tissues were significantly increased in the model group (P<0.01). After EA intervention, the decreased levels of the FVC, FEV0.1, FEV0.3, FEV0.1/FVC and FEV0.3/FVC, and the increased levels of the abovementioned genes and proteins were all reversed in the EA group (P<0.01, P<0.05). After modeling, the bronchial walls were thickened, with enlarged alveolar cavities, fractured alveolar walls, obvious inflammatory cell infiltration, and rich mucus secretion in the lumen, which was relatively milder in the EA group. CONCLUSION: EA of ST36 can improve the ventilation function in COPD rats, which may be associated with its function in down-regulating the levels of TNF-α, TGF-α, IL-8, EGFR, p38MAPK and MUC5AC mRNAs and proteins in the lung tissues, inhibiting EGFR-p38MAPK signaling mediated expression of MUC5AC.


Asunto(s)
Electroacupuntura , Enfermedad Pulmonar Obstructiva Crónica , Animales , Receptores ErbB/genética , Inflamación , Pulmón , Masculino , Mucina 5AC , Enfermedad Pulmonar Obstructiva Crónica/genética , Enfermedad Pulmonar Obstructiva Crónica/terapia , Ratas , Ratas Sprague-Dawley , Proteínas Quinasas p38 Activadas por Mitógenos/genética
4.
Crit Rev Oncol Hematol ; 160: 103300, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33744362

RESUMEN

Since their discovery, relevant efforts have been made to optimize the detection approaches to EGFR mutations as well as the clinical management of EGFR-mutated NSCLC. The recent shift from single gene testing to novel comprehensive detection platforms along with the development of new generation tyrosine kinase inhibitors, targeting both common and uncommon EGFR-mutations, is leading to a progressive increase in the number of patients who may benefit from targeted approaches, with subsequent impact on their long-term survival and quality of life. However, a prompt and adequate implementation of the most recent diagnostic and treatment advances in the routine practice often remains critical to be specifically addressed. In this review we provide a complete and updated overview of the different detection platforms and therapeutic options currently available for the clinical management of advanced EGFR-positive NSCLC, summarizing scientific evidence and describing molecular testing as well as treatment practice in the real-word scenario.


Asunto(s)
Neoplasias Pulmonares , Calidad de Vida , Receptores ErbB/genética , Humanos , Italia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Mutación , Inhibidores de Proteínas Quinasas/uso terapéutico
5.
Crit Rev Oncol Hematol ; 160: 103305, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33757838

RESUMEN

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are treatments commonly used for lung cancer. The toxicity profile including toxicity incidence, severity, and spectrum (involving various specific adverse events) of each EGFR-TKI are of particular clinical interest and importance. Data from phase II and III randomized controlled trials comparing treatments among EGFR-TKIs (osimertinib, dacomitinib, afatinib, erlotinib, gefitinib, and icotinib) and chemotherapy for lung cancer were synthesized with Bayesian network meta-analysis. The primary outcome was systemic all-grade and grade ≥3 adverse events. The secondary outcome was specific all-grade adverse events including those of the skin, gastrointestinal tract, lung, etc. 40 trials randomizing 13,352 patients were included. Generally greater toxicity for dacomitinib and afatinib, and safety for icotinib were suggested. Furthermore, we found individual EGFR-TKIs had different toxicity spectrums. These findings provide a compelling safety reference for the individualized use of EGFR-TKIs for patients with lung cancer.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Teorema de Bayes , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Mutación , Metaanálisis en Red , Inhibidores de Proteínas Quinasas/efectos adversos
8.
Cochrane Database Syst Rev ; 3: CD010383, 2021 03 18.
Artículo en Inglés | MEDLINE | ID: mdl-33734432

RESUMEN

BACKGROUND: Epidermal growth factor receptor (EGFR) mutation positive (M+) non-small cell lung cancer (NSCLC) is an important subtype of lung cancer comprising 10% to 15% of non-squamous tumours. This subtype is more common in women than men, is less associated with smoking, but occurs at a younger age than sporadic tumours. OBJECTIVES: To assess the clinical effectiveness of single-agent or combination EGFR therapies used in the first-line treatment of people with locally advanced or metastatic EGFR M+ NSCLC compared with other cytotoxic chemotherapy (CTX) agents used alone or in combination, or best supportive care (BSC). The primary outcomes were overall survival and progression-free survival. Secondary outcomes included response rate, symptom palliation, toxicity, and health-related quality of life. SEARCH METHODS: We conducted electronic searches of the Cochrane Register of Controlled Trials (CENTRAL) (2020, Issue 7), MEDLINE (1946 to 27th July 2020), Embase (1980 to 27th July 2020), and ISI Web of Science (1899 to 27th July 2020). We also searched the conference abstracts of the American Society for Clinical Oncology and the European Society for Medical Oncology (July 2020); Evidence Review Group submissions to the National Institute for Health and Care Excellence; and the reference lists of retrieved articles. SELECTION CRITERIA: Parallel-group randomised controlled trials comparing EGFR-targeted agents (alone or in combination with cytotoxic agents or BSC) with cytotoxic chemotherapy (single or doublet) or BSC in chemotherapy-naive patients with locally advanced or metastatic (stage IIIB or IV) EGFR M+ NSCLC unsuitable for treatment with curative intent. DATA COLLECTION AND ANALYSIS: Two review authors independently identified articles, extracted data, and carried out the 'Risk of bias' assessment. We conducted meta-analyses using a fixed-effect model unless there was substantial heterogeneity, in which case we also performed a random-effects analysis as a sensitivity analysis. MAIN RESULTS: Twenty-two trials met the inclusion criteria. Ten of these exclusively recruited people with EGFR M+ NSCLC; the remainder recruited a mixed population and reported results for people with EGFR M+ NSCLC as subgroup analyses. The number of participants with EGFR M+ tumours totalled 3023, of whom approximately 2563 were of Asian origin. Overall survival (OS) data showed inconsistent results between the included trials that compared EGFR-targeted treatments against cytotoxic chemotherapy or placebo. Erlotinib was used in eight trials, gefitinib in nine trials, afatinib in two trials, cetuximab in two trials, and icotinib in one trial. The findings of FASTACT 2 suggested a clinical benefit for OS for participants treated with erlotinib plus cytotoxic chemotherapy when compared to cytotoxic chemotherapy alone, as did the Han 2017 trial for gefitinib plus cytotoxic chemotherapy, but both results were based on a small number of participants (n = 97 and 122, respectively). For progression-free survival (PFS), a pooled analysis of four trials showed evidence of clinical benefit for erlotinib compared with cytotoxic chemotherapy (hazard ratio (HR) 0.31; 95% confidence interval (CI) 0.25 to 0.39 ; 583 participants ; high-certainty evidence). A pooled analysis of two trials of gefitinib versus paclitaxel plus carboplatin showed evidence of clinical benefit for PFS for gefitinib (HR 0.39; 95% CI 0.32 to 0.48 ; 491 participants high-certainty evidence), and a pooled analysis of two trials of gefitinib versus pemetrexed plus carboplatin with pemetrexed maintenance also showed evidence of clinical benefit for PFS for gefitinib (HR 0.59; 95% CI 0.46 to 0.74, 371 participants ; moderate-certainty evidence). Afatinib showed evidence of clinical benefit for PFS when compared with chemotherapy in a pooled analysis of two trials (HR 0.42; 95% CI 0.34 to 0.53, 709 participants high-certainty evidence). All but one small trial showed a corresponding improvement in response rate with tyrosine-kinase inhibitor (TKI) compared to chemotherapy. Commonly reported grade 3/4 adverse events associated with afatinib, erlotinib, gefitinib and icotinib monotherapy were rash and diarrhoea. Myelosuppression was consistently worse in the chemotherapy arms; fatigue and anorexia were also associated with some chemotherapies. Seven trials reported on health-related quality of life and symptom improvement using different methodologies. For each of erlotinib, gefitinib, and afatinib, two trials showed improvement in one or more indices for the TKI compared to chemotherapy. The quality of evidence was high for the comparisons of erlotinib and gefitinib with cytotoxic chemotherapy and for the comparison of afatinib with cytotoxic chemotherapy. AUTHORS' CONCLUSIONS: Erlotinib, gefitinib, afatinib and icotinib are all active agents in EGFR M+ NSCLC patients, and demonstrate an increased tumour response rate and prolonged PFS compared to cytotoxic chemotherapy. We found a beneficial effect of the TKI compared to cytotoxic chemotherapy in adverse effect and health-related quality of life. We found limited evidence for increased OS for the TKI when compared with standard chemotherapy, but the majority of the included trials allowed participants to switch treatments on disease progression, which will have a confounding effect on any OS analysis. Single agent-TKI remains the standard of care and the benefit of combining a TKI and chemotherapy remains uncertain as the evidence is based on small patient numbers. Cytotoxic chemotherapy is less effective in EGFR M+ NSCLC than erlotinib, gefitinib, afatinib or icotinib and is associated with greater toxicity. There are no data supporting the use of monoclonal antibody therapy. Icotinib is not available outside China.


Asunto(s)
Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Receptores ErbB/genética , Neoplasias Pulmonares/tratamiento farmacológico , Mutación , Afatinib/efectos adversos , Afatinib/uso terapéutico , Anciano , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Sesgo , Carboplatino/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Cetuximab/efectos adversos , Cetuximab/uso terapéutico , Éteres Corona/efectos adversos , Éteres Corona/uso terapéutico , Clorhidrato de Erlotinib/efectos adversos , Clorhidrato de Erlotinib/uso terapéutico , Femenino , Gefitinib/efectos adversos , Gefitinib/uso terapéutico , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Paclitaxel/uso terapéutico , Pemetrexed/uso terapéutico , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Calidad de Vida , Quinazolinas/efectos adversos , Quinazolinas/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto
10.
Eur J Med Chem ; 216: 113297, 2021 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-33677351

RESUMEN

Antibody-drug conjugates (ADCs) are currently among the most successful and important strategies for treating patients with solid tumors. ADCs are composed of a monoclonal antibody and warhead, which are conjugated via a linker. Currently, monomethyl auristatin E (MMAE) is the most widely applied warhead in the development of ADCs. However, MMAE-based ADCs are generally constructed using the MC-VC-PABC linker, and this design has limited structural diversity and some disadvantages. Accordingly, in this study, we generated three types of novel linker-MMAE (with alterations in the spacer, catabolizing area, and self-immolative compared with MC-VC-PABC-MMAE) in ADCs, termed SCT200-linker-MMAE conjugates, and then evaluated the linker-drug plasma stability and the rate of drug release by cathepsin B. The binding ability, internalization rates, and efficacy of all SCT200-linker-MMAE ADCs were systematically studied, and the expression of apoptosis-associated proteins and the therapeutic efficacies of SCT200-M-2, -C-2, and -C-4 were evaluated. The results showed that the activities of some of these ADCs were increased for epidermal growth factor receptor-positive tumors. Moreover, the novel linkers designed in this study can be linked with other antibodies to treat other types of cancer. Overall, these findings provide important insights into the application of SCT200-based linkers in ADCs.


Asunto(s)
Anticuerpos Monoclonales/química , Antineoplásicos/síntesis química , Inmunoconjugados/química , Oligopéptidos/química , Animales , Antineoplásicos/sangre , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Catepsina B/metabolismo , Línea Celular Tumoral , Liberación de Fármacos , Estabilidad de Medicamentos , Receptores ErbB/genética , Receptores ErbB/inmunología , Receptores ErbB/metabolismo , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Inmunoconjugados/sangre , Inmunoconjugados/farmacología , Inmunoconjugados/uso terapéutico , Ratones , Ratones Desnudos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Oligopéptidos/metabolismo , Ensayos Antitumor por Modelo de Xenoinjerto
11.
Life Sci ; 273: 119292, 2021 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-33667516

RESUMEN

Delta opioids are thought to relieve ischemic injury and have tissue-protective properties. However, the detailed mechanisms of delta opioids have not been well identified. Receptor tyrosine kinases (RTKs), such as epidermal growth factor receptor (EGFR), have been shown to mediate downstream signals of δ opioid receptor (δOR) activation through the metalloproteinase (MMP)-dependent EGF-like growth factor (HB-EGF) excretion pathway, which is called transactivation. In this study, to investigate the role of EGFR in δOR-induced anti-ischemic effects in the brain, we applied the middle cerebral artery occlusion (MCAO) model followed by reperfusion to mimic ischemic stroke injury in rats. Pre-treatment with the δOR agonist [D-ala2, D-leu5] enkephalin (DADLE) improved the neurologic deficits and the decreased infarct volume caused by cerebral ischemia/reperfusion injury, which were blocked by the EGFR inhibitor AG1478 and the MMP inhibitor GM6001, respectively. Further results indicated that DADLE activated EGFR, Akt and ERK1/2 and upregulated EGFR expression in the hippocampus in a time-dependent manner, which were inhibited by AG1478 and GM6001. The enzyme-linked immunosorbent assay (ELISA) results showed that δOR activation led to an increase in HB-EGF release, but HB-EGF in tissue was downregulated at the mRNA and protein levels. Moreover, this protective action caused by δOR agonists may involve attenuated hippocampal cellular apoptosis. Overall, these results demonstrate that MMP-mediated transactivation of EGFR is essential for δOR agonist-induced MCAO/reperfusion injury relief. These findings provide a potential molecular mechanism for the neuroprotective property of δOR and may add new insight into mitigating or preventing injury.


Asunto(s)
Isquemia Encefálica/prevención & control , Leucina Encefalina-2-Alanina/farmacología , Receptores ErbB/metabolismo , Infarto de la Arteria Cerebral Media/complicaciones , Receptores Opioides delta/agonistas , Daño por Reperfusión/prevención & control , Activación Transcripcional , Animales , Apoptosis , Isquemia Encefálica/etiología , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patología , Receptores ErbB/genética , Masculino , Fosforilación , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión/etiología , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología
12.
Medicine (Baltimore) ; 100(10): e19713, 2021 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-33725808

RESUMEN

BACKGROUND: Latest clinical trials have proved the better overall survival (OS) for the use of immune checkpoint inhibitors verse chemotherapy in non-small cell lung cancer (NSCLC) patients. However, we still have no clear ideas of the factors which could affect the efficacy of immune checkpoint inhibitors. Cancer, essentially, is a disease related to genes mutation. Therefore, we conducted a systematic review and meta-analysis to compare efficacy of immune checkpoint inhibitors for NSCLC patients with different genes mutation. METHODS: PubMed, EMBASE, Web of Science, and the Cochrane Library databases were searched for all clinical trials in NSCLC until December 16, 2019. The hazard ratio (HR) and 95% confidence intervals (CIs) of OS or progression-free survival (PFS) were used. RESULTS: A total of 4453 patients from 7 randomized controlled trials (RCTs) were included. Immune checkpoint inhibitors significantly prolonged the OS (HR, 0.67; 95% CI, 0.60-0.67) in NSCLC patients having epidermal growth factor receptor (EGFR) wild-type versus chemotherapy. Meanwhile, they prolonged the OS (HR, 0.61; 95% CI, 0.39-0.94) in NSCLC patients with Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation. No matter PD-L1 tumor proportion scores were >1% or <1%, immune checkpoint inhibitors were more effective than chemotherapy (HR, 0.64; 95% CI, 0.55-0.75). CONCLUSION: Immune checkpoint inhibitors are more efficacious than chemotherapy in NSCLC patients with EGFR wild-type, KRAS mutation, and any PD-L1 tumor proportion scores.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Antígeno B7-H1/genética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/mortalidad , Mutación , Supervivencia sin Progresión , Proteínas Proto-Oncogénicas p21(ras)/genética , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de Tiempo
13.
Medicine (Baltimore) ; 100(10): e25046, 2021 Mar 12.
Artículo en Inglés | MEDLINE | ID: mdl-33725888

RESUMEN

RATIONALE: Genotypic and histological evolution of non-small-cell lung cancer (NSCLC) into small-cell lung cancer (SCLC) has been described as a mechanism of acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy. However, the number of clinical cases is rare. PATIENT CONCERNS: Two lung adenocarcinoma patients with EGFR mutations who recurred after radical resection transformed into SCLC under treatment with the sequential first- and third-generation EGFR-TKIs. DIAGNOSIS: The 2 cases were both confirmed as SCLC by pathological rebiopsy after EGFR-TKIs resistance. INTERVENTIONS: Case 1 was treated with etoposide plus cisplatin (EP) regimen and erlotinib, while case 2 was treated with erlotinib and EP followed by oral etoposide. OUTCOMES: Case 1 treated with EP only achieved 3-month progression-free survival (PFS), which is the first case that reported T790 M/C797S cis-mutation for osimertinib resistance before the SCLC transformation. However, case 2 treated with erlotinib and EP followed by oral etoposide, PFS lasted for 8 months. LESSONS: The cases highlighted the importance of rebiopsy that identified pathologically SCLC transformation after EGFR-TKI resistance, and suggested the treatment of erlotinib plus EP followed by etoposide, which could provide a reference for such phenotype.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/terapia , Neoplasias Pulmonares/patología , Recurrencia Local de Neoplasia/terapia , Inhibidores de Proteínas Quinasas/farmacología , Carcinoma Pulmonar de Células Pequeñas/terapia , Acrilamidas/farmacología , Acrilamidas/uso terapéutico , Adulto , Compuestos de Anilina/farmacología , Compuestos de Anilina/uso terapéutico , Biopsia , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Cisplatino/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Epirrubicina/uso terapéutico , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Clorhidrato de Erlotinib/uso terapéutico , Resultado Fatal , Femenino , Humanos , Pulmón/diagnóstico por imagen , Pulmón/patología , Pulmón/cirugía , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Neumonectomía , Inhibidores de Proteínas Quinasas/uso terapéutico , Carcinoma Pulmonar de Células Pequeñas/diagnóstico , Carcinoma Pulmonar de Células Pequeñas/genética , Carcinoma Pulmonar de Células Pequeñas/patología , Tomografía Computarizada por Rayos X , Resultado del Tratamiento
14.
Clinics (Sao Paulo) ; 76: e2251, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33787673

RESUMEN

OBJECTIVES: Lung cancer is the leading cause of cancer-related deaths worldwide. However, factors associated with the survival of patients with advanced non-small-cell lung cancer (NSCLC) who received only hospice care are largely unclear. In this study, we aimed to determine the prognostic factors correlated with survival in patients with advanced NSCLC who had undergone hospice care only. METHODS: A total of 102 patients with recurrent stage III/IV NSCLC after traditional treatment failure were investigated. Survival was measured from the date of enrollment to December 2019 or the time of death. Tumor tissues were collected, and DNA sequencing was performed to identify somatic mutations. Data on clinical factors of patients were collected and analyzed by univariate and multivariate analyses. Overall survival analysis was conducted using the Kaplan-Meier method. RESULTS: The 6-month, 1-year, and 2-year overall survival rates of the 102 patients with metastatic NSCLC were 17.65%, 3.92%, and 0.98%, respectively. The median overall survival of the 102 patients was 3.15 months. Tumor location in the peripheral lung, epidermal growth factor receptor (EGFR) inhibitor history, low tumor mutation load, adenocarcinoma, and poor performance status score were associated with prolonged survival compared with tumor location in the central lung, no EGFR inhibitor history, high tumor mutation load, squamous cell carcinoma, and good performance status score (p=0.045, p=0.003, p=0.045, p=0.021, and p=0.0003, respectively). CONCLUSIONS: EGFR inhibitor treatment history and tumor mutation load are risk factors for the overall survival of patients with stage III/IV NSCLC who have undergone only hospice care. These results provide a critical clinical basis for further study of nontraditional anti-tumor responses induced by EGFR inhibitors.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Mutación , Estadificación de Neoplasias , Pronóstico , Inhibidores de Proteínas Quinasas/uso terapéutico , Estudios Retrospectivos
15.
Medicine (Baltimore) ; 100(11): e24793, 2021 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-33725945

RESUMEN

INTRODUCTION: It has been well reported that non-small-cell lung cancer (NSCLC) patients with single epithelial growth factor receptor (EGFR) activating mutation have high objective response rate when treated with EGFR-TKIs. However, due to rarity of cases, the response of patients with EGFR double or multiple mutations is not yet well understood. Patient-derived organoid technology has become to a powerful tool in cancer personalized medicine. PATIENT CONCERNS: A 60-year-old nonsmoking female was admitted to hospital for lung cancer after Chest CT. DIAGNOSES: The patient had no obvious clinical symptoms. Postoperative pathology confirmed a stage I of NSCLC. An EGFR double mutation 19Del/L643V was detected in the sequence of patient's cancer specimen. INTERVENTIONS: The patient was in good condition after surgical resection, with no sign of lung cancer recurrence. The patient has not yet started on targeted medicine. OUTCOMES: A lung cancer organoid culture was established from the cancer tissue of the patient, which recapitulated the morphological and molecular characteristics of cancer tissue. The drug sensitivity test showed that the cancer organoids that retained original mutations were sensitive to anticancer agents osimertinib and gefitinib, while resistant to erlotinib and icotinib. CONCLUSION: The uncommon EGFR double mutation exhibits distinctive sensitivities towards different target drugs of EGFR-TKIs. Our findings provide a better understanding of EGFR-TKIs' effects on patient-derived cancer organoids harboring uncommon EGFR double mutation(s).


Asunto(s)
Adenocarcinoma del Pulmón/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Variantes Farmacogenómicas , Acrilamidas/uso terapéutico , Adenocarcinoma del Pulmón/genética , Compuestos de Anilina/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/genética , Receptores ErbB/genética , Femenino , Gefitinib/uso terapéutico , Humanos , Neoplasias Pulmonares/genética , Persona de Mediana Edad , Mutación
16.
Nat Cell Biol ; 23(3): 278-291, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33664496

RESUMEN

Activated EGFR signalling drives tumorigenicity in 50% of glioblastoma (GBM). However, EGFR-targeting therapy has proven ineffective in treating patients with GBM, indicating that there is redundant EGFR activation. Circular RNAs are covalently closed RNA transcripts that are involved in various physiological and pathological processes. Herein, we report an additional activation mechanism of EGFR signalling in GBM by an undescribed secretory E-cadherin protein variant (C-E-Cad) encoded by a circular E-cadherin (circ-E-Cad) RNA through multiple-round open reading frame translation. C-E-Cad is overexpressed in GBM and promotes glioma stem cell tumorigenicity. C-E-Cad activates EGFR independent of EGF through association with the EGFR CR2 domain using a unique 14-amino-acid carboxy terminus, thereby maintaining glioma stem cell tumorigenicity. Notably, inhibition of C-E-Cad markedly enhances the antitumour activity of therapeutic anti-EGFR strategies in GBM. Our results uncover a critical role of C-E-Cad in stimulating EGFR signalling and provide a promising approach for treating EGFR-driven GBM.


Asunto(s)
Antígenos CD/metabolismo , Neoplasias Encefálicas/enzimología , Cadherinas/metabolismo , Glioblastoma/enzimología , ARN Circular/metabolismo , Factor de Transcripción STAT3/metabolismo , Animales , Antígenos CD/genética , Antineoplásicos/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patología , Cadherinas/genética , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Glioblastoma/tratamiento farmacológico , Glioblastoma/genética , Glioblastoma/patología , Humanos , Ratones Desnudos , Invasividad Neoplásica , ARN Circular/genética , Factor de Transcripción STAT3/genética , Transducción de Señal , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto
17.
Anticancer Res ; 41(3): 1261-1269, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-33788717

RESUMEN

BACKGROUND/AIM: Non-small cell lung cancer patients with epidermal growth factor receptor (EGFR) mutation have been shown to have a good response to erlotinib, a receptor tyrosine kinase inhibitor of EGFR. In this study, we found that the cell death pathways activated by erlotinib in 2D and 3D culture systems are different. MATERIALS AND METHODS: The cell death pathways induced by erlotinib were evaluated by flow cytometry and immunoblotting in both 2D and 3D culture systems of EGFR mutant lung cancer cells. RESULTS: Treatment with erlotinib induced caspase 8 activation and up-regulation of TNF-related apoptosis-inducing ligand (TRAIL) expression only in 3D cultures. Knockdown of TRAIL attenuated both erlotinib-induced activation of caspase-8 and apoptosis in 3D cultures. Erlotinib also increased LC3, an autophagy marker, expression and c-Jun N terminal kinase (JNK) activation. Both 3-MA as an autophagy inhibitor and SP600125 as a JNK inhibitor, significantly inhibited erlotinib-induced cell death. CONCLUSION: Erlotinib induces apoptotic cell death in 3D cultures through an autophagy-TRAIL-JNK pathway.


Asunto(s)
Técnicas de Cultivo de Célula/métodos , Clorhidrato de Erlotinib/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Mutación , Apoptosis/efectos de los fármacos , Autofagia/fisiología , Caspasa 8/metabolismo , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Clorhidrato de Erlotinib/uso terapéutico , Humanos , Proteínas Quinasas JNK Activadas por Mitógenos/fisiología , Neoplasias Pulmonares/patología , Ligando Inductor de Apoptosis Relacionado con TNF/fisiología
18.
Methods Mol Biol ; 2279: 109-126, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33683689

RESUMEN

Driver mutations in non-small cell lung cancer (NSCLC) have a relevant significance for clinical management. EGFR mutations are the most important predictive biomarkers for NSCLC, although KRAS and BRAF mutations can also be prognostic and predictive biomarkers, respectively. PCR-based approaches followed by sequencing are useful for EGFR, KRAS, and BRAF mutational analysis. Herein, all steps for a PCR-based technique, from DNA isolation from tumor tissue sections to DNA sequencing for genetic analysis of EGFR, KRAS, and BRAF hotspot regions are described.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , Reacción en Cadena de la Polimerasa , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Análisis Mutacional de ADN , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/patología
19.
Methods Mol Biol ; 2279: 127-144, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33683690

RESUMEN

The profiling of EGFR mutations, the most common genetic alterations in non-small cell lung cancer (NSCLC) predictive of targeted therapy efficacy, is crucial to anticipate the patient response to EGFR tyrosine kinase inhibitors. Here, we introduce the naica® system for 6-color Crystal Digital PCRTM and describe in detail a standardized workflow for the multiplexed, single-assay detection of the 19 most prevalent sensitizing and resistance EGFR mutations in both tumor and circulating tumor DNA (ctDNA) samples. Two major advantages of the 6-color multiplexing system over current digital PCR systems are the rapid time to results, and the large quantity of mutational information obtained per patient sample, rendering the 6-color system highly cost effective. The 6-color Crystal Digital PCRTM technology enables highly sensitive and efficient therapeutic monitoring through liquid biopsy, resulting in the early detection of treatment resistance. While the assay presented here specifically addresses EGFR mutation status monitoring in NSCLC patients, 6-color Crystal Digital PCRTM assays are flexible and evolutive in design. As such, 6-color detection assays can be optimized to monitor mutations associated with a range of cancers and other genetic diseases, as well as to detect genetic changes beyond the oncology and human health domains.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/genética , ADN Tumoral Circulante/genética , Neoplasias Pulmonares/genética , Reacción en Cadena de la Polimerasa Multiplex , Proteínas de Neoplasias/genética , Carcinoma de Pulmón de Células no Pequeñas/sangre , ADN Tumoral Circulante/sangre , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/sangre , Mutación
20.
Nat Commun ; 12(1): 1628, 2021 03 12.
Artículo en Inglés | MEDLINE | ID: mdl-33712615

RESUMEN

Tyrosine kinase inhibitors were found to be clinically effective for treatment of patients with certain subsets of cancers carrying somatic mutations in receptor tyrosine kinases. However, the duration of clinical response is often limited, and patients ultimately develop drug resistance. Here, we use single-cell RNA sequencing to demonstrate the existence of multiple cancer cell subpopulations within cell lines, xenograft tumors and patient tumors. These subpopulations exhibit epigenetic changes and differential therapeutic sensitivity. Recurrently overrepresented ontologies in genes that are differentially expressed between drug tolerant cell populations and drug sensitive cells include epithelial-to-mesenchymal transition, epithelium development, vesicle mediated transport, drug metabolism and cholesterol homeostasis. We show analysis of identified markers using the LINCS database to predict and functionally validate small molecules that target selected drug tolerant cell populations. In combination with EGFR inhibitors, crizotinib inhibits the emergence of a defined subset of EGFR inhibitor-tolerant clones. In this study, we describe the spectrum of changes associated with drug tolerance and inhibition of specific tolerant cell subpopulations with combination agents.


Asunto(s)
Resistencia a Antineoplásicos/genética , Tolerancia a Medicamentos/genética , Tolerancia a Medicamentos/fisiología , Neoplasias/genética , Neoplasias/metabolismo , Antineoplásicos/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Colesterol/metabolismo , Combinación de Medicamentos , Descubrimiento de Drogas , Transición Epitelial-Mesenquimal/genética , Receptores ErbB/efectos de los fármacos , Receptores ErbB/genética , Regulación Neoplásica de la Expresión Génica , Xenoinjertos , Humanos , Mutación , Neoplasias/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Tirosina Quinasas Receptoras/metabolismo , Células U937
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