Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

KIF5B-RET fusions have recently been reported to occur in pulmonary adenocarcinomas, thereby being proposed as a novel genetic alteration in adenocarcinoma of the lung. However, clinically useful methods to detect RET-rearrangement in pulmonary adenocarcinoma have not been well established. 53 cases of lung adenocarcinomas harbored "triple (EGFR, KRAS and ALK)-negative" were tested for KIF5B-RET fusions using whole-transcriptome sequencing, fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), and long-range PCR. Dual color break-apart probes and KIF5B-RET fusion probes were used for FISH. Three different commercial antibodies against C-terminal RET protein were tested for IHC. Primers designed for 3 different variants of KIF5B-RET fusions were used for long-range PCR. Three patients (5.6%) showed RET rearrangement in whole-transcriptome sequencing, which were used as a gold standard. All those three patients were also positive in FISH for both KIF5B-RET fusion and RET break-apart probes. None of remaining patients showed positive result, resulting in 100% concordance rate of FISH and transcriptome sequencing methods. However, fused RET proteins were not detected by IHC in none of true positive patients. Moreover, 6 patients without RET fusions showed gain of gene copy number of both KIF5B and RET. All those three true positive cases were detected by long-range PCR methods and none with true negative cases were positive. Both FISH and PCR may be useful methods to detect novel KIF5B-RET rearrangements in pulmonary adenocarcinomas rather than IHC. However, as there may be additional variant of fusion mutation, FISH may be better than PCR method in terms of sensitivity.
Lung Cancer 2013 Oct
PMID:Diagnostic method for the detection of KIF5B-RET transformation in lung adenocarcinoma. 2393 63

Non-small cell lung carcinoma (NSCLC) is the most common subtype of lung cancer. The oncogenic potential of receptor tyrosine kinases (RTKs) is widely known and they are potential targets for tailored therapy. Ephrin receptors (Ephs) form the largest group of RTKs. Nevertheless, Ephs are not widely studied in NSCLC so far. The aim of our study was to investigate novel mutations of Eph genes (EPHA1-8, EPHB1-4, EPHB6) and their association with clinically relevant mutations in BRAF, EML4-ALK, EGFR, INSR, KDR, KRAS, MET, PDGFRA, PDGFRB, PIK3, PTEN, RET, and TP53 in NSCLC patients. Targeted resequencing was conducted on 81 formalin-fixed, paraffin-embedded NSCLC tumor specimens. We analyzed missense and nonsense mutations harbored in the coding regions of the selected genes. We found 18 novel mutations of Ephs in 20% (16 of 81) of the patients. Nearly half of these mutations occurred in the protein kinase domain. The mutations were not mutually exclusive with other clinically relevant mutations. Our study shows that Ephs are frequently mutated in NSCLC patients, and occur together with other known mutations relevant to the pathogenicity of NSCLC.
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PMID:Mutated ephrin receptor genes in non-small cell lung carcinoma and their occurrence with driver mutations-targeted resequencing study on formalin-fixed, paraffin-embedded tumor material of 81 patients. 2412 10

Lung adenocarcinomas have diverse genetic and morphological backgrounds and are usually classified according to their distinct oncogenic mutations (or so-called driver mutations) and histological subtypes (the de novo classification proposed by the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society [IASLC/ATS/ERS]). Although both these classifications are essential for personalized treatment, their integrated clinical effect remains unclear. Therefore, we analyzed 981 lung adenocarcinomas to detect the potential correlation and combined effect of oncogenic mutations and histological subtype on prognosis. Analysis for oncogenic mutations included the direct sequencing of EGFR, KRAS, HER2, BRAF, PIK3CA, ALK, and RET for oncogenic mutations/rearrangements, and a rereview of the IASLC/ATS/ERS classification was undertaken. Eligible tumors included 13 atypical adenomatous hyperplasia/adenocarcinoma in situ, 20 minimally invasive adenocarcinomas, 901 invasive adenocarcinomas, 44 invasive mucinous adenocarcinomas, and three other variants. The invasive mucinous adenocarcinomas had a lower prevalence of EGFR mutations but a higher prevalence of KRAS, ALK, and HER2 mutations than invasive adenocarcinomas. Smoking, a solid predominant pattern, and a mucinous component were independently associated with fewer EGFR mutations. The ALK rearrangements were more frequently observed in tumors with a minor mucinous component, while the KRAS mutations were more prevalent in smokers. In addition, 503 patients with stage I-IIIA tumors were analyzed for overall survival (OS) and relapse-free survival. The stage and histological pattern were independent predictors of relapse-free survival, and the pathological stage was the only independent predictor for the OS. Although patients with the EGFR mutations had better OS than those without the mutations, no oncogenic mutation was an independent predictor of survival. Oncogenic mutations were associated with the novel IASLC/ATS/ERS classification, which facilitates a morphology-based mutational analysis strategy. The combination of these two classifications might not increase the prognostic ability, but it provides essential information for personalized treatment.
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PMID:Oncogenic mutations are associated with histological subtypes but do not have an independent prognostic value in lung adenocarcinoma. 2515 23

Rearrangements of ROS1 and RET have been recently described as new driver mutations in lung adenocarcinoma with a frequency of about 1% each. RET and ROS1 rearrangements both represent unique molecular subsets of lung adenocarcinoma with virtually no overlap with other known driver mutations described so far in lung adenocarcinoma. Specific clinicopathologic characteristics have been described and several multitargeted receptor kinase inhibitors have shown in vitro activity against NSCLC cells harbouring these genetic alterations. In addition, the MET/ALK/ROS inhibitor crizotinib has already shown impressive clinical activity in patients with advanced ROS1-positive lung cancer. Currently, several early proof of concept clinical trials are testing various kinase inhibitors in both molecular subsets of lung adenocarcinoma patients. Most probably, personalized treatment of these genetically defined new subsets of lung adenocarcinoma will be implemented in routine clinical care of lung cancer patients in the near future.
Transl Lung Cancer Res 2013 Apr
PMID:Activated RET and ROS: two new driver mutations in lung adenocarcinoma. 2580 22

Metastatic non-small cell lung cancer (NSCLC) unfortunately remains a lethal disease, despite recent genetic characterization of subclasses of NSCLC, mainly adenocarcinoma, which has led to the development of targeted therapies that improve progression-free survival (PFS). Ultimately, however, patients fatally relapse. In this review we will focus on the search to improve survival for NSCLC patients deemed to be pan-negative for the common driver alterations susceptible to targeted therapy, above all those with EGFR mutations or ALK, ROS or RET translocations. Other uncommon driver mutations such as HER2 and BRAF mutations should be tested in order to rule out targeted treatment before assigning patients to chemotherapy. Chemotherapy yields short lived response with median survival still less than one year. Customized chemotherapy represents one way to attempt to prolong survival, although to date no prospective randomized customized studies have reported sufficient evidence to support this. In one attempt to demonstrate the role of tailoring chemotherapy, the Spanish Lung Cancer Group (SLCG) phase II customized chemotherapy trial (NCT00883480) showed that RAP80, a component of the BRCA1-A complex, influenced outcome in patients with low BRCA1 expression treated with cisplatin/gemcitabine, and in patients with intermediate/high BRCA1 levels receiving cisplatin/docetaxel or docetaxel alone. We are currently performing a prospective, randomized phase III trial comparing non-customized cisplatin/docetaxel with customized therapy in metastatic NSCLC patients (NCT00617656/GECP-BREC) and a parallel phase II study (ChiCTR-TRC-12001860) is being carried out in China (BREC-China) under the auspices of the SLCG.
Transl Lung Cancer Res 2013 Jun
PMID:Customized chemotherapy in metastatic non-small cell lung cancer (NSCLC). 2580 31

Recent advances in lung cancer genomics have successfully characterized therapeutic targets of lung cancer. RET fusion gene products are among the newest target molecules for lung adenocarcinoma. Preclinical findings and preliminary reports regarding potential tumor control by RET-targeting multi-kinase inhibitors encourage further clinical trials. The infrequent prevalence of RET fusion gene-positive cases may be a major obstacle hindering the development of RET-targeted therapy. Thus, it is necessary to recruit appropriate participants for trials to develop an efficient RET fusion gene detection system to achieve targeted therapy for lung adenocarcinomas stratified by this molecular target.
Transl Lung Cancer Res 2013 Dec
PMID:RET-targeting molecular stratified non-small-cell lung cancers. 2580 72

Somatic mutational profiling in cancer has revolutionized the practice of clinical oncology. The discovery of driver mutations in non-small cell lung cancer (NSCLC) is an example of this. Molecular testing of lung adenocarcinoma is now considered standard of care and part of the diagnostic algorithm. This article provides an overview of the workflow of molecular testing in a clinical diagnostic laboratory discussing in particular novel assays that are currently in use for somatic mutation detection in NSCLC focussing on epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK), ROS1 and RET rearrangements.
Transl Lung Cancer Res 2015 Apr
PMID:Molecular methods for somatic mutation testing in lung adenocarcinoma: EGFR and beyond. 2587 Jul 95

Fusions of the RET and ROS1 protein tyrosine kinase oncogenes with several partner genes were recently identified as new targetable genetic aberrations in cases of non-small cell lung cancer (NSCLC) lacking activating EGFR, KRAS, ALK, BRAF, or HER2 oncogene aberrations. RET and ROS1 fusion-positive tumors are mainly observed in young, female, and/or never smoking patients. Studies based on in vitro and in vivo (i.e., mouse) models and studies of several fusion-positive patients indicate that inhibiting the kinase activity of the RET and ROS1 fusion proteins is a promising therapeutic strategy. Accordingly, there are several ongoing clinical trials aimed at examining the efficacy of tyrosine kinase inhibitors (TKIs) against RET and ROS1 proteins in patients with fusion-positive lung cancer. Other gene fusions (NTRK1, NRG1, and FGFR1/2/3) that are targetable by existing TKIs have also been identified in NSCLCs. Options for personalized lung cancer therapy will be increased with the help of multiplex diagnosis systems able to detect multiple druggable gene fusions.
Transl Lung Cancer Res 2015 Apr
PMID:Beyond ALK-RET, ROS1 and other oncogene fusions in lung cancer. 2587 Jul 98

In-frame fusion KIF5B (the-kinesin-family-5B-gene)-RET transcripts have been characterized in 1-2% of non-small cell lung cancers and are known oncogenic drivers. The RET tyrosine kinase inhibitor, vandetanib, suppresses fusion-induced, anchorage-independent growth activity. In vitro studies have shown that vandetanib is a high-affinity substrate of breast cancer resistance protein (Bcrp1/Abcg2) but is not transported by P-glycoprotein (P-gp), limiting its blood-brain barrier penetration. A co-administration strategy to enhance the brain accumulation of vandetanib by modulating P-gp/Abcb1- and Bcrp1/Abcg2-mediated efflux with mTOR inhibitors, specifically everolimus, was shown to increase the blood-brain barrier penetration. We report the first bench-to-bedside evidence that RET inhibitor combined with an mTOR inhibitor is active against brain-metastatic RET-rearranged lung cancer and the first evidence of blood-brain barrier penetration. A 74-year-old female with progressive adenocarcinoma of the lung (wild-type EGFR and no ALK rearrangement) presented for therapy options. A deletion of 5'RET was revealed by FISH assay, indicating RET-gene rearrangement. Because of progressive disease in the brain, she was enrolled in a clinical trial with vandetanib and everolimus (NCT01582191). Comprehensive genomic profiling revealed fusion of KIF5B (the-kinesin-family-5B-gene) and RET, in addition to AKT2 gene amplification. After two cycles of therapy a repeat MRI brain showed a decrease in the intracranial disease burden and PET/CT showed systemic response as well. Interestingly, AKT2 amplification seen is a critical component of the PI3K/mTOR pathway, alterations of which has been associated with both de novo and acquired resistance to targeted therapy. The addition of everolimus may have both overcome the AKT2 amplification to produce a response in addition to its direct effects on the RET gene. Our case report forms the first evidence of blood-brain barrier penetration by vandetanib in combination with everolimus. Further research is required in this setting.
Lung Cancer 2015 Jul
PMID:Systemic and CNS activity of the RET inhibitor vandetanib combined with the mTOR inhibitor everolimus in KIF5B-RET re-arranged non-small cell lung cancer with brain metastases. 2598 12

The two clinically validated and Food and Drug Administration approved lung cancer predictive biomarkers (epidermal growth factor receptor mutations and anaplastic lymphoma kinase (ALK) translocations) occur in only about 20 % of lung adenocarcinomas and acquired resistance develops to first generation drugs. Several other oncogenic drivers for lung adenocarcinoma have emerged as potentially druggable targets with new predictive biomarkers. Oncologists are requesting testing for ROS1 translocations which predict susceptibility to crizotinib, already approved for ALK positive lung cancers. Other potential biomarkers which are currently undergoing clinical trials are RET, MET, HER2 and BRAF. Detection of these biomarkers includes fluorescent in situ hybridization and/or reverse transcriptase polymerase chain reaction (ROS1, RET, HER2), mutation analysis (BRAF) and immunohistochemistry (MET). Screening by immunohistochemistry may be useful for some biomarkers (ROS1, BRAF). Targeted next generation sequencing techniques may be useful as well. These five biomarkers are under consideration for inclusion in revised lung cancer biomarker guidelines by the College of American Pathologists, International Association for the Study of Lung Cancer and Association for Molecular Pathology.
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PMID:Emerging Biomarkers in Personalized Therapy of Lung Cancer. 2670 97


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