RESUMEN
According to currently available estimates from Cancer Research UK, 14.1 million new lung cancer cases were diagnosed and a staggering 8.2 million people worldwide died from lung cancer in 2012. EGFR and c-Met are two tyrosine kinase receptors most commonly overexpressed or mutated in Non-small Cell Lung Cancer (NSCLC) resulting in increased proliferation and survival of lung cancer cells. Tyrosine kinase inhibitors (TKIs), such as erlotinib, approved by the FDA as first/second line therapy for NSCLC patients have limited clinical efficacy due to acquired resistance. In this manuscript, we investigate and discuss the role of epithelial mesenchymal transition (EMT) in the development of resistance against EGFR and c-Met TKIs in NSCLC. Our findings show that Zeb-1, a transcriptional repressor of E-Cadherin, is upregulated in TKI-resistant cells causing EMT. We observed that TKI-resistant cells have increased gene and protein expression of EMT related proteins such as Vimentin, N-Cadherin, ß-Catenin and Zeb-1, while expression of E-Cadherin, an important cell adhesion molecule, was suppressed. We also confirmed that TKI-resistant cells display mesenchymal cell type morphology, and have upregulation of ß-Catenin which may regulate expression of Zeb-1, a transcriptional repressor of E-Cadherin in TKI-resistant NSCLC cells. Finally, we show that down-regulating Zeb-1 by inducing miR-200a or ß-Catenin siRNA can increase drug sensitivity of TKI-resistant cells.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Transición Epitelial-Mesenquimal/efectos de los fármacos , Receptores ErbB/metabolismo , Neoplasias Pulmonares/metabolismo , Inhibidores de Proteínas Quinasas/administración & dosificación , Proteínas Tirosina Quinasas Receptoras/metabolismo , Antineoplásicos/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Línea Celular Tumoral , Resistencia a Antineoplásicos , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Resultado del TratamientoRESUMEN
Surgery, radiation therapy, and chemotherapy are the traditional options to control tumor progression. However, these strategies are fraught with harmful side effects and are ineffective in metastatic and advanced cancers. Biomarkers that are overexpressed in cancers and are involved in cell growth, proliferation, migration, and survival have recently become the focus of new molecular targeting therapies. Novel therapies targeting biomarkers have roles in tumorigenesis that are overexpressed in cancers may be more efficacious and less toxic in comparison to traditional therapies. These therapies include the use of tyrosine kinase inhibitors and monoclonal antibodies for the treatment of cancer. However, the efficacy of these therapies is limited due to the development of drug resistance after prolonged treatment. Current research is focused on understanding mechanisms of resistance to overcome the barriers limiting the use of these targeting therapies in the treatment of cancer. In this review, we will discuss the clinical status of tyrosine kinase inhibitors and monoclonal antibodies against several prevalent biomarkers that are candidates for therapy in non-small cell lung cancer (NSCLC) and melanoma.
Asunto(s)
Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Melanoma/tratamiento farmacológico , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/farmacología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Resistencia a Antineoplásicos , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Melanoma/metabolismo , Melanoma/patología , Terapia Molecular Dirigida , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/metabolismo , Transducción de SeñalRESUMEN
Numerous tyrosine kinase inhibitors (TKIs) targeting c-Met are currently in clinical trials for several cancers. Their efficacy is limited due to the development of resistance. The present study aims to elucidate this mechanism of c-Met TKI resistance by investigating key mTOR and Wnt signaling proteins in melanoma cell lines resistant to SU11274, a c-Met TKI. Xenografts from RU melanoma cells treated with c-Met TKIs SU11274 and JNJ38877605 showed a 7- and 6-fold reduction in tumor size, respectively. Resistant cells displayed upregulation of phosphorylated c-Met, mTOR, p70S6Kinase, 4E-BP1, ERK, LRP6, and active ß-catenin. In addition, GATA-6, a Wnt signaling regulator, was upregulated, and Axin, a negative regulator of the Wnt pathway, was downregulated in resistant cells. Modulation of these mTOR and Wnt pathway proteins was also prevented by combination treatment with SU11274, everolimus, an mTOR inhibitor, and XAV939, a Wnt inhibitor. Treatment with everolimus, resulted in 56% growth inhibition, and a triple combination of SU11274, everolimus and XAV939, resulted in 95% growth inhibition in RU cells. The V600E BRAF mutation was found to be positive only in MU cells. Combination treatment with a c-Met TKI and a BRAF inhibitor displayed a synergistic effect in reducing MU cell viability. These studies indicate activation of mTOR and Wnt signaling pathways in c-Met TKI resistant melanoma cells and suggest that concurrent targeting of c-Met, mTOR, and Wnt pathways and BRAF may improve efficacy over traditional TKI monotherapy in melanoma patients.