ABSTRACT
Multiple randomized studies have demonstrated improved response rates, progression-free survival, and quality of life for treatment-naive, advanced-stage adenocarcinoma patients harboring sensitizing EGFR mutations when they are treated with tyrosine kinase inhibitor therapy, as compared with chemotherapy. Despite improved outcomes with these agents, the majority of patients will eventually develop resistance and subsequent clinical progression. Recently, there has been a firmer understanding of the molecular mechanisms of the resistance that develops as a consequence of treatment, most notably the identification of a second-site EGFR mutation, T790M. While this understanding can inform subsequent treatment decisions, disease progression can be heterogeneous, and there are several competing therapeutic options. Treatment decisions must consider this clinical heterogeneity, factoring in the pace of disease growth, lung cancer-related symptoms, and the potential presence of T790M mutations. Herein, we review the available literature addressing these competing strategies and attempt to clarify best treatment practices, including the emerging role of T790M-directed therapies.
Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Agents/therapeutic use , Biomarkers, Tumor/genetics , Drug Resistance, Neoplasm , ErbB Receptors/genetics , Lung Neoplasms/drug therapy , Mutation , Protein Kinase Inhibitors/therapeutic use , Protein-Tyrosine Kinases/antagonists & inhibitors , Adenocarcinoma/enzymology , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Disease Progression , Drug Resistance, Neoplasm/drug effects , Humans , Lung Neoplasms/enzymology , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Neoplasm Staging , Quality of Life , Randomized Controlled Trials as Topic , Treatment OutcomeABSTRACT
We have previously reported intra-segmental crossovers in Brome mosaic virus (BMV) RNAs. In this work, we studied the homologous recombination of BMV RNA in three different hosts: barley (Hordeum vulgare), Chenopodium quinoa, and Nicotiana benthamiana that were co-infected with two strains of BMV: Russian (R) and Fescue (F). Our work aimed at (1) establishing the frequency of recombination, (2) mapping the recombination hot spots, and (3) addressing host effects. The F and R nucleotide sequences differ from each other at many translationally silent nucleotide substitutions. We exploited this natural variability to track the crossover sites. Sequencing of a large number of cDNA clones revealed multiple homologous crossovers in each BMV RNA segment, in both the whole plants and protoplasts. Some recombination hot spots mapped at similar locations in different hosts, suggesting a role for viral factors, but other sites depended on the host. Our results demonstrate the chimeric ('mosaic') nature of the BMV RNA genome.
