RESUMEN
The emergence of acquired resistance limits the long-term efficacy of EGFR tyrosine kinase inhibitors (EGFR TKIs). Thus, development of effective strategies to overcome resistance to EGFR TKI is urgently needed. Multiple mechanisms to reactivate ERK signaling have been successfully demonstrated in acquired resistance models. We found that in EGFR mutant non-small cell lung cancer (NSCLC) patients, acquired resistance to EGFR TKIs was accompanied by increased activation of ERK. Increased ERK activation was also found in in vitro models of acquired EGFR TKI resistance. ASN007 is a potent selective ERK1/2 inhibitor with promising antitumor activity in cancers with BRAF and RAS mutations. ASN007 treatment impeded tumor cell growth and the cell cycle in EGFR TKI-resistant cells. In addition, combination treatment with ASN007 and EGFR TKIs significantly decreased the survival of resistant cells, enhanced induction of apoptosis, and effectively inhibited the growth of erlotinib-resistant xenografts, providing the preclinical rationale for testing combinations of ASN007 and EGFR TKIs in EGFR-mutated NSCLC patients. This study emphasizes the importance of targeting ERK signaling in maintaining the long-term benefits of EGFR TKIs by overcoming acquired resistance.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Resistencia a Antineoplásicos , Receptores ErbB , Humanos , Neoplasias Pulmonares/patología , Mutación , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Although immune checkpoint inhibitors have significantly improved clinical outcomes in various malignant cancers, only a small proportion of patients reap benefits, likely due to the low number of T cells and high number of immunosuppressive cells in the tumor microenvironment (TME) of patients with advanced disease. We developed a cancer vaccine adjuvanted with nanoemulsion (NE) loaded with TLR7/8 agonist (R848) and analyzed its therapeutic effect alone or in combination with immune checkpoint inhibitors, on antitumor immune responses and the reprogramming of suppressive immune cells in the TME. NE (R848) demonstrated robust local and systemic antitumor immune responses in both subcutaneous and orthotopic mouse lung cancer models, inducing tumor-specific T cell activation and mitigating T cell exhaustion. Combination with anti-PD-1 antibodies showed synergistic effects with respect to therapeutic efficacy and survival rate. Thus, NE (R848)-based cancer vaccines could prevent tumor recurrence and prolong survival by activating antitumor immunity and reprogramming immunosuppression.
Asunto(s)
Vacunas contra el Cáncer/farmacología , Neoplasias Pulmonares/terapia , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor Toll-Like 7/genética , Receptor Toll-Like 8/genética , Adyuvantes Inmunológicos/farmacología , Animales , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Vacunas contra el Cáncer/química , Vacunas contra el Cáncer/inmunología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Emulsiones/química , Emulsiones/farmacología , Humanos , Imidazoles/farmacología , Inhibidores de Puntos de Control Inmunológico/farmacología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Activación de Linfocitos/efectos de los fármacos , Ratones , Receptor de Muerte Celular Programada 1/inmunología , Receptor Toll-Like 7/agonistas , Receptor Toll-Like 8/agonistas , Microambiente Tumoral/efectos de los fármacosRESUMEN
Antitumor immune responses induced by immune checkpoint inhibitors anti-PD-1 or anti-PD-L1 have been used as therapeutic strategies in advanced non-small cell lung cancer (NSCLC) patients over the last decade. Favorable antitumor activity to immune checkpoint inhibitors is correlated with high PD-L1 expression, increased tumor-infiltrating lymphocytes, and decreased suppressive immune cells including Treg cells, myeloid-derived suppressor cells, or tumor-associated macrophages in various cancer types. In this study, we investigated the potential correlation between clinical outcomes and peripheral blood immune cell profiles, specifically focused on FoxP3+ Treg cells, collected at baseline and one week after anti-PD-1 therapy in two independent cohorts of patients with NSCLC: a discovery cohort of 83 patients and a validation cohort of 49 patients. High frequencies of circulating Treg cells one week after anti-PD-1 therapy were correlated with a high response rate, longer progression-free survival, and overall survival. Furthermore, high levels of TGF-ß and Treg cells were associated with favorable clinical outcomes. Our results suggest that higher levels of FoxP3+ Treg cells and TGF-ß can predict a favorable response to anti-PD-1 immunotherapy in patients with advanced NSCLC.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Factores de Transcripción Forkhead/metabolismo , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Linfocitos T Reguladores/metabolismo , Factor de Crecimiento Transformador beta/genética , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/farmacología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Estudios de Cohortes , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Masculino , Persona de Mediana Edad , Nivolumab/administración & dosificación , Nivolumab/farmacología , Análisis de Supervivencia , Linfocitos T Reguladores/efectos de los fármacos , Factor de Crecimiento Transformador beta/metabolismo , Resultado del Tratamiento , Microambiente Tumoral/efectos de los fármacosRESUMEN
Salvia miltiorrhiza root has been used in Asian traditional medicine for the treatment of cardiovascular diseases, asthma, and other conditions. Salvianolic acid B from S. miltiorrhiza extracts has been shown to improve airway hyperresponsiveness. We investigated the effects of salvianolic acid A, tanshinone I, and tanshinone IIA from S. miltiorrhiza in allergic asthma by using rat RBL-2H3 mast cells and female Balb/c mice. Antigen-induced degranulation was assessed by measuring ß-hexosaminidase activity in vitro. In addition, a murine ovalbumin-induced allergic asthma model was used to test the in vivo efficacy of salvianolic acid A and tanshinone IIA. Tanshinone I and tanshinone IIA inhibited antigen-induced degranulation of mast cells, but salvianolic acid A did not. Administration of salvianolic acid A and tanshinone IIA decreased the number of immune cells, particularly eosinophils in allergic asthma-induced mice. Histological studies showed that salvianolic acid A and tanshinone IIA reduced mucin production and inflammation in the lungs. Administration of salvianolic acid A and tanshinone IIA reduced the expression and secretion of Th2 cytokines (IL-4 and IL-13) in the bronchoalveolar lavage fluid and lung tissues of mice with ovalbumin-induced allergic asthma. These findings provide evidence that salvianolic acid A and tanshinone IIA may be potential anti-allergic therapeutics.
Asunto(s)
Abietanos/uso terapéutico , Antialérgicos/uso terapéutico , Ácidos Cafeicos/uso terapéutico , Hipersensibilidad/tratamiento farmacológico , Lactatos/uso terapéutico , Mastocitos/fisiología , Animales , Degranulación de la Célula , Línea Celular , Citocinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Mucinas/metabolismo , Ratas , Salvia miltiorrhiza/inmunología , Células Th2/inmunología , beta-N-Acetilhexosaminidasas/metabolismoRESUMEN
Sphingosine kinase 1 and its product, sphingosine 1-phosphate (S1P), as well as their receptors, have been implicated in inflammatory responses. The functions of receptors S1P1 and S1P2 on cell motility have been investigated. However, the function of S1P3 has been poorly investigated. In this study, the roles of S1P3 on inflammatory response were investigated in primary peritoneal macrophages. S1P3 receptor was induced along with sphingosine kinase 1 by stimulation of lipopolysaccharide (LPS). LPS treatment induced inflammatory genes, such iNOS, COX-2, IL-1ß, IL-6 and TNF-α. TY52156, an antagonist of S1P3 suppressed the induction of inflammatory genes in a concentration dependent manner. Suppression of iNOS and COX-2 induction was further confirmed by western blotting and NO measurement. Suppression of IL-1ß induction was also confirmed by western blotting and ELISA. Caspase 1, which is responsible for IL-1ß production, was similarly induced by LPS and suppressed by TY52156. Therefore, we have shown S1P3 induction in the inflammatory conditions and its pro-inflammatory roles. Targeting S1P3 might be a strategy for regulating inflammatory diseases.