RESUMEN
Epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) is clinically and genetically heterogeneous, with concurrent RB1/TP53 mutations, indicating an increased risk of transformation into small cell lung cancer (SCLC). When tumor cells convert into a different histological subtype, they lose their dependence on the original oncogenic driver, resulting in therapeutic resistance. However, the molecular details associated with this transformation remain unclear. It has been difficult to define molecular mechanisms of neuroendocrine (NE) transformation in lung cancer due to a lack of pre- and post-transformation clinical samples. In this study, we established a NSCLC cell line with concurrent RB1/TP53 mutations and built corresponding patient-derived xenograft (PDX) models to investigate the mechanisms underlying transformation to SCLC. Studying these PDX models, we demonstrate that EGFR loss facilitates lineage plasticity of lung adenocarcinoma initiated by biallelic mutations of TP53 and RB1. Gene expression analysis of these EGFR knockout tumors revealed altered expression of neuroendocrine synapse-associated lineage genes. There is an increased expression of epigenetic reprogramming factors like Sox2 and gene associated with neural development like NTRK in these EGFR knockout tumors. These findings uncovered the role of EGFR in the acquisition of plasticity, which is the ability of a cell to substantially modify its identity and take on a new phenotype, and defined a novel landscape of potential drivers of NE transformation in lung cancer.
Asunto(s)
Adenocarcinoma del Pulmón , Carcinoma de Pulmón de Células no Pequeñas , Receptores ErbB , Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Adenocarcinoma del Pulmón/patología , Carcinoma de Pulmón de Células no Pequeñas/patología , Receptores ErbB/genética , Neoplasias Pulmonares/patología , Mutación , Inhibidores de Proteínas Quinasas/uso terapéutico , Carcinoma Pulmonar de Células Pequeñas/patología , AnimalesRESUMEN
Multifunctional core/shell micelles were self-assembled from triblock copolymers poly(ethylene glycol) methyl ether-b-peptide-g-cholesterol (mPEG-b-P-g-Chol) and used as the doxorubicin delivery carriers for cancer chemotherapy. The copolymers were designed and synthesized successfully based on peptides containing histidine residues (pH-trigger) with different topological structures. The peptides were modified by mPEG (hydrophilic) and cholesterol motifs (hydrophobic) on the terminus, resulting in pH-sensitive amphiphilic copolymers. The critical micelle concentrations (CMCs) of the micelles were determined as 4.79, 2.50 and 1.86mg/L for the linear, Y-shape and fork-shape copolymers, respectively, demonstrating the formation of micelle even at low concentration. The pKb values of three copolymers were found to be around 6.1-6.3 by potentiometric titration test, showing the satisfied pH-sensitivity. The average diameter and zeta potential of blank micelles were 170nm and +20mV at pH 7.4, and increased to 250nm and +35mV at pH 5.0. DOX was loaded into the core of polymeric micelles by dialysis method, and the drug loading capacity slightly increased when the copolymer topological structure changed from linear to Y- and fork-shape. The drug release rate from the system was obviously influencing by the pH values according to the results of in vitro DOX release experiment. Moreover, to investigate the structure-property relationship, the drug release mechanism was preliminarily explored by the semi-empirical equations. Toxicity test showed that three copolymers had bare toxicity whereas the DOX-loaded micelles remained high cytotoxicity for tumor cells. The results indicate the synthesized copolymers might be a potential hydrophobic drug delivery carrier for cancer targeting therapy with controlled drug release.