RESUMO
Osimertinib (Osi) is widely used as a first-line treatment for non-small cell lung cancer (NSCLC) with EGFR mutations. However, the majority of patients treated with Osi eventually relapse within a year. The mechanisms of Osi resistance remain largely unexplored, and efficient strategies to reverse the resistance are urgently needed. Here, we developed a lactoferrin-modified liposomal codelivery system for the combination therapy of Osi and panobinostat (Pan), an epigenetic regulator of histone acetylation. We demonstrated that the codelivery liposomes could efficiently repolarize tumor-associated macrophages (TAM) from the M2 to M1 phenotype and reverse the epithelial-mesenchymal transition (EMT)-associated drug resistance in the tumor cells, as well as suppress glycolysis, lactic acid production, and angiogenesis. Our results suggested that the combination therapy of Osi and Pan mediated by liposomal codelivery is a promising strategy for overcoming Osi resistance in NSCLC.
Assuntos
Acrilamidas , Compostos de Anilina , Carcinoma Pulmonar de Células não Pequenas , Resistencia a Medicamentos Antineoplásicos , Epigênese Genética , Indóis , Neoplasias Pulmonares , Panobinostat , Inibidores de Proteínas Quinases , Pirimidinas , Humanos , Acrilamidas/farmacologia , Acrilamidas/uso terapêutico , Compostos de Anilina/farmacologia , Compostos de Anilina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/genética , Lipossomos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Panobinostat/farmacologia , Panobinostat/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/patologiaRESUMO
Breast cancer is the most commonly diagnosed malignancy in women. Several key genes and pathways have been proven to correlate with breast cancer pathology. This study sought to explore the differences in key transcription factors (TFs), transcriptional regulation networks and dysregulated pathways in different tissues in breast cancer. We employed 14 breast cancer datasets from NCBI-GEO and performed an integrated analysis in three different tissues including breast, blood and saliva. The results showed that there were eight genes (CEBPD, EGR1, EGR2, EGR3, FOS, FOSB, ID1 and NFIL3) down-regulated in breast tissue but up-regulated in blood tissue. Furthermore, we identified several unreported tissue-specific TFs that may contribute to breast cancer, including ATOH8, DMRT2, TBX15 and ZNF367. The dysregulation of these TFs damaged lipid metabolism, development, cell adhesion, proliferation, differentiation and metastasis processes. Among these pathways, the breast tissue showed the most serious impairment and the blood tissue showed a relatively moderate damage, whereas the saliva tissue was almost unaffected. This study could be helpful for future biomarker discovery, drug design, and therapeutic and predictive applications in breast cancers.