ABSTRACT
Activating point mutations in the MET tyrosine kinase domain (TKD) are oncogenic in a subset of papillary renal cell carcinomas. Here, using comprehensive genomic profiling among >600,000 patients, we identify activating MET TKD point mutations as putative oncogenic driver across diverse cancers, with a frequency of â¼0.5%. The most common mutations in the MET TKD defined as oncogenic or likely oncogenic according to OncoKB resulted in amino acid substitutions at positions H1094, L1195, F1200, D1228, Y1230, M1250, and others. Preclinical modeling of these alterations confirmed their oncogenic potential and also demonstrated differential patterns of sensitivity to type I and type II MET inhibitors. Two patients with metastatic lung adenocarcinoma harboring MET TKD mutations (H1094Y, F1200I) and no other known oncogenic drivers achieved confirmed partial responses to a type I MET inhibitor. Activating MET TKD mutations occur in multiple malignancies and may confer clinical sensitivity to currently available MET inhibitors. Significance: The identification of targetable genomic subsets of cancer has revolutionized precision oncology and offers patients treatments with more selective and effective agents. Here, we demonstrate that activating, oncogenic MET tyrosine kinase domain mutations are found across a diversity of cancer types and are responsive to MET tyrosine kinase inhibitors.
Subject(s)
Lung Neoplasms , Point Mutation , Protein Kinase Inhibitors , Proto-Oncogene Proteins c-met , Humans , Proto-Oncogene Proteins c-met/genetics , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Lung Neoplasms/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/pharmacology , Animals , Mice , Cell Line, TumorABSTRACT
OBJECTIVES: Prior research suggests that the presence of state-specific pediatric emergency medical facility recognition programs (PFRPs) is associated with high emergency department (ED) pediatric readiness. The PFRPs aim to improve the quality of pediatric emergency care, but individual state programs differ. We aimed to describe the variation in PFRP characteristics and verification requirements and to describe the availability of pediatric emergency care coordinators (PECCs) in states with PFRPs. METHODS: In mid-2020, we collected information about each PFRP from 3 sources: the state Emergency Medical Services for Children (EMSC) website, the EMSC Innovation and Improvement Center website, or via communication with the state's EMSC program manager. For each state with a PFRP, we documented program characteristics, including program start date, number of tiers, whether participation was required/optional, and requirements for verification. RESULTS: Overall, we identified 17 states with active PFRPs. Five states had only 1 tier or level of recognition whereas the others had multiple. All programs did require presence of a PECC for verification. However, some PRFPs with multiple verification tiers did not require presence of a PECC to achieve each level of verification. In states with PFRPs, EDs with higher total visit volumes, a separate pediatric ED area, located in the Northeast, and earlier program start date were all more likely to have a PECC. CONCLUSIONS: There is variation in state PFRPs, although all prioritize the presence of a PECC. We encourage further research on the effect of different aspects of PFRPs on patient outcomes.
Subject(s)
Disaster Planning , Emergency Medical Services , Child , Humans , United States , Emergency Service, HospitalABSTRACT
OBJECTIVE: A common opportunity to collect research samples is during image-guided percutaneous core needle biopsies (CNBs) performed when clinically indicated or for assessing clinical trial eligibility. The relative safety of extra CNBs collected for research is undefined. MATERIALS AND METHODS: Patients who underwent CNB for research purposes only [RO], as clinically indicated [CI], or as part of a clinical trial [CT] were identified. 30-day post-procedure adverse events (AEs) among the cohorts were examined and compared to the 2020 Society of Interventional Radiology QI guidelines. RESULTS: 236 patients with thoracic cancers (90 % NSCLC, 5 % SCLC, 4 % mesothelioma, and 1 % thymic) had 292 CNBs (63 RO, 229 CI + CT). AEs occurred in 13 % of both the RO and CI + CT groups. Compared to the CI + CT group, the RO group did not have a higher pneumothorax incidence (RO: 5/29 [17 %], CI + CT: 18/114 [16 %], p = 0.79); both were below the suggested QI threshold of 45 % for pneumothorax. There was a negative association between number of cores obtained and risk of AE (AE vs no AE mean cores = 3.5 vs 4.8). After adjusting for the number of cores and smoking history, RO vs CI + CT lung biopsies had a higher risk of AEs (adjusted relative risk [aRR] = 2.44, 1.08-5.55, p = 0.03 vs non-lung aRR = 0.86, 0.10-7.09, p = 0.89). CONCLUSION: CNBs performed for research purposes do not have a significantly increased risk of AEs when compared to those performed for clinical trials and/or when clinically indicated. However, AEs were most frequent in lung biopsies. When performing research biopsies, a target other than lung may be preferred when clinically appropriate.
Subject(s)
Lung Neoplasms , Pneumothorax , Thoracic Neoplasms , Humans , Image-Guided Biopsy/adverse effects , Image-Guided Biopsy/methods , Lung Neoplasms/pathology , Pneumothorax/epidemiology , Pneumothorax/etiology , Tomography, X-Ray Computed , Clinical Trials as TopicABSTRACT
The clinical significance of gene fusions detected by DNA-based next generation sequencing remains unclear as resistance mechanisms to EGFR tyrosine kinase inhibitors in EGFR mutant non-small cell lung cancer. By studying EGFR inhibitor-resistant patients treated with a combination of an EGFR inhibitor and a drug targeting the putative resistance-causing fusion oncogene, we identify patients who benefit and those who do not from this treatment approach. Through evaluation including RNA-seq of potential drug resistance-imparting fusion oncogenes in 504 patients with EGFR mutant lung cancer, we identify only a minority of them as functional, potentially capable of imparting EGFR inhibitor resistance. We further functionally validate fusion oncogenes in vitro using CRISPR-based editing of EGFR mutant cell lines and use these models to identify known and unknown drug resistance mechanisms to combination therapies. Collectively, our results partially reveal the complex nature of fusion oncogenes as potential drug resistance mechanisms and highlight approaches that can be undertaken to determine their functional significance.