SummaryA large number of metabolites are found in each plant, most of which have not yet been identified. Development of a methodology is required to deal systematically with unknown metabolites, and to elucidate their biological roles in an integrated 'omics' framework. Here we report the development of a 'metabolite annotation' procedure. The metabolite annotation is a process by which structures and functions are inferred for metabolites. Tomato (Solanum lycopersicum cv. Micro-Tom) was used as a model for this study using LC-FTICR-MS. Collected mass spectral features, together with predicted molecular formulae and putative structures, were provided as metabolite annotations for 869 metabolites. Comparison with public databases suggests that 494 metabolites are novel. A grading system was introduced to describe the evidence supporting the annotations. Based on the comprehensive characterization of tomato fruit metabolites, we identified chemical building blocks that are frequently found in tomato fruit tissues, and predicted novel metabolic pathways for flavonoids and glycoalkaloids. These results demonstrate that metabolite annotation facilitates the systematic analysis of unknown metabolites and biological interpretation of their relationships, which provide a basis for integrating metabolite information into the system-level study of plant biology.
LAG-3 is expressed on TILs in tumor tissues of some patients with NSCLC. Its expression was higher in nonadenocarcinoma and correlated with PD-1/PD-L1 expression. LAG-3 positivity or both LAG-3 and PD-L1 positivity was correlated with early postoperative recurrence. LAG-3 was related to poor prognosis.
This is the first report of a relationship between EMT and erlotinib acquired resistance in an erlotinib sensitive EGFR-mutant lung cancer cell line. Our results indicate that it would be important to consider the influence of EMT in the development of treatments against acquired resistance to gefitinib or erlotinib.
KRAS and epidermal growth factor receptor (EGFR) are the two most frequently mutated proto-oncogenes in adenocarcinoma of the lung. The occurrence of these two oncogenic mutations is mutually exclusive, and they exhibit many contrasting characteristics such as clinical background, pathological features of patients harboring each mutation, and prognostic or predictive implications. Lung cancers harboring the EGFR mutations are remarkably sensitive to EGFR tyrosine kinase inhibitors such as gefitinib or erlotinib. This discovery has dramatically changed the clinical treatment of lung cancer in that it almost doubled the duration of survival for lung cancer patients with an EGFR mutation. In this review, we describe the features of KRAS mutations in lung cancer and contrast these with the features of EGFR mutations. Recent strategies to combat lung cancer harboring KRAS mutations are also reviewed.
Introduction: KRAS mutations have been recognized as undruggable for many years. Recently, novel KRAS G12C inhibitors, such as sotorasib and adagrasib, are being developed in clinical trials and have revealed promising results in metastatic NSCLC. Nevertheless, it is strongly anticipated that acquired resistance will limit their clinical use. In this study, we developed in vitro models of the KRAS G12C cancer, derived from resistant clones against sotorasib and adagrasib, and searched for secondary KRAS mutations as on-target resistance mechanisms to develop possible strategies to overcome such resistance.Methods: We chronically exposed Ba/F3 cells transduced with KRAS G12C to sotorasib or adagrasib in the presence of N-ethyl-N-nitrosourea and searched for secondary KRAS mutations. Strategies to overcome resistance were also investigated.Results: We generated 142 Ba/F3 clones resistant to either sotorasib or adagrasib, of which 124 (87%) harbored secondary KRAS mutations. There were 12 different secondary KRAS mutations. Y96D and Y96S were resistant to both inhibitors. A combination of novel SOS1 inhibitor, BI-3406, and trametinib had potent activity against this resistance. Although G13D, R68M, A59S and A59T, which were highly resistant to sotorasib, remained sensitive to adagrasib, Q99L was resistant to adagrasib but sensitive to sotorasib.
Conclusions:We identified many secondary KRAS mutations causing resistance to sotorasib, adagrasib, or both, in vitro. The differential activities of these two inhibitors depending on the secondary mutations suggest sequential use in some cases. In addition, switching to BI-3406 plus trametinib might be a useful strategy to overcome acquired resistance owing to the secondary Y96D and Y96S mutations.
Our highly sensitive CH method showed that a subgroup of non-small-cell lung cancer patients with the EGFR mutation harbored the rare T790M allele before EGFR-TKI treatment. A high proportion of T790M allele may define a clinical subset with a relatively favorable prognosis.
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