Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lung cancer is the leading cause of cancer-related death, with non-small cell lung cancer (NSCLC) being the predominant form of the disease. Most lung cancer is caused by the accumulation of genomic alterations due to tobacco exposure. To uncover its mutational landscape, we performed whole-exome sequencing in 31 NSCLCs and their matched normal tissue samples. We identified both common and unique mutation spectra and pathway activation in lung adenocarcinomas and squamous cell carcinomas, two major histologies in NSCLC. In addition to identifying previously known lung cancer genes (TP53, KRAS, EGFR, CDKN2A and RB1), the analysis revealed many genes not previously implicated in this malignancy. Notably, a novel gene CSMD3 was identified as the second most frequently mutated gene (next to TP53) in lung cancer. We further demonstrated that loss of CSMD3 results in increased proliferation of airway epithelial cells. The study provides unprecedented insights into mutational processes, cellular pathways and gene networks associated with lung cancer. Of potential immediate clinical relevance, several highly mutated genes identified in our study are promising druggable targets in cancer therapy including ALK, CTNNA3, DCC, MLL3, PCDHIIX, PIK3C2B, PIK3CG and ROCK2.
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PMID:Identification of somatic mutations in non-small cell lung carcinomas using whole-exome sequencing. 2251 Feb 80

Considerable progress has been achieved in the understanding of lung cancer biology. Molecular driver mutations have been identified and different targeted therapies have been developed. Thus, the management of small size biopsies is essential and needs a strong collaboration between the different medical partners, particularly pulmonologist, pathologist, molecular biologist and oncologist. The aim is to optimise histological and molecular analyses allowing patients access to novel biotherapies. The French National Cancer Institute set up platforms for molecular genetics at university hospitals with expertise in molecular and pathological analysis. Mutational status of EGFR is analyzed routinely in non-small lung cancer. Treatment with EGFR inhibitors as first line therapy is limited to lung cancer patients harboring an EGFR mutation. More recently, ALK rearrangements have been identified as a rare driver mutation in lung cancer. Crizotinib, an ALK inhibitor is a new therapeutic standard in ALK rearranged tumors. Other biomarkers as RAS, BRAF, HER2 or PIK3CA have potential clinical relevance with possible approval of novel tailored treatment and will be discussed in this report. The project "BIOMARQUEURS France" will underscore the results of the French platform of more than 15 000 French patients.
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PMID:[Which platform to support a personalized lung cancer treatment?]. 2252 2

Despite improvements in cancer therapies in the past 50 years, neuroblastoma remains a devastating clinical problem and a leading cause of childhood cancer deaths. Advances in treatments for children with high-risk neuroblastoma have, until recently, involved addition of cytotoxic therapy to dose-intensive regimens. In this era of targeted therapies, substantial efforts have been made to identify optimal targets for different types of cancer. The discovery of hereditary and somatic activating mutations in the oncogene ALK has now placed neuroblastoma among other cancers, such as melanoma and non-small-cell lung cancer (NSCLC), which benefit from therapies with oncogene-specific small-molecule tyrosine kinase inhibitors. Crizotinib, a small-molecule inhibitor of ALK, has transformed the landscape for the treatment of NSCLC harbouring ALK translocations and has demonstrated activity in preclinical models of ALK-driven neuroblastomas. However, inhibition of mutated ALK is complex when compared with translocated ALK and remains a therapeutic challenge. This Review discusses the biology of ALK in the development of neuroblastoma, preclinical and clinical progress with the use of ALK inhibitors and immunotherapy, challenges associated with resistance to such therapies and the steps being taken to overcome some of these hurdles.
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PMID:Targeting ALK in neuroblastoma--preclinical and clinical advancements. 2258 2

In 2007, the ALK tyrosine kinase was described as a potential therapeutic target for a subset of non-small-cell lung cancer patients. Clinical proof of concept, culminating in the recent approval by the Food and Drug Administration of the Pfizer drug crizotinib followed in record time. The drug was approved together with a companion diagnostic for detection of patients eligible for therapy. This remarkable example of the coming of age of personalized medicine in cancer therapy is hopefully only an auspice of things to come in a rapidly developing field. Perhaps unsurprisingly, however, the appearance of clinical acquired resistance to crizotinib was observed early on in clinical testing, with the identification of several ALK secondary point mutations which diminish drug efficacy and which open the way for development of second-generation inhibitors. It is also emerging that acquired resistance to crizotinib may additionally occur through ALK-independent mechanisms, which still need to be elucidated in detail. Here we discuss the factors that led to such a rapid approval of a targeted agent, and we describe the second-generation compounds currently in development.
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PMID:ALK Inhibitors, a Pharmaceutical Perspective. 2265 63

Non-small-cell lung cancer (NSCLC) is the leading cause of cancer-specific death in the USA and Europe. Over the last two decades, the pathogenetic mechanisms and the molecular alterations of NSCLC have been investigated more intensively, a number of potential therapeutic targets have been identified and new agents against specific molecular targets have been introduced in the treatment of NSCLC. Acquired abnormalities in the genes encoding RAS, p53, KRAS, EGFR and ALK, are particularly important in this field. Whenever targetable mutations are not found, the research of other genetic abnormalities can be useful to personalize chemotherapy. The attention has been focused, in particular, on the endonuclease excision repair cross-complementing1 and BRCA1 status. The use of antimetabolite drugs and the level of expression of their cellular targets seem to be correlated and influence the clinical efficacy of those agents. This review will focus on the role of predictive biomarkers for the treatment of non-small cell lung cancer.
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PMID:Molecular and clinical analysis of predictive biomarkers in non-small-cell lung cancer. 2268 Sep 28

The oncologist dream is to provide more benefit with lower toxicity. The increasing knowledge of molecular mechanism for survival and proliferation of cancer cells leads to the development of targeted therapies with impressive results for some cancers even if not associated with chemotherapy. These targeted treatments could be monoclonal antibodies or tyrosine kinase inhibitors. Inactivation of only one oncogene can lead to the regression of tumours as well as the inhibition of only one pathway with one or more inhibitors. This result is related to the oncogenic addiction of these tumours. Examples are imatinib in CML and GIST, trastuzumab in HER2 positive breast cancer, gefitinib in mutated EGFR, crizotinib in EML4-ALK positive lung cancer and, also, vemurafenib in BRAF 600E mutated metastatic melanoma. We shall specifically discuss HER2 positive breast cancer, which represent some 15-20% of breast cancers and the recent targeted and bi-targeted therapies. Trastuzumab, an anti-HER2 monoclonal antibody has changed the prognosis of the disease improving survival in the metastatic and adjuvant setting. Lapatinib, a dual tyrosine kinase inhibitor of EGFR and HER2 is approved with capecitabine in trastuzumab resistant patients and in combination with letrozole in first line. Unfortunately, 20% of patients receiving adjuvant trastuzumab relapse and metastatic patients only transienly respond to trastuzumab or lapatinib combined with chemotherapy. New HER2 targeted drugs are currently in development like pertuzumab, T-DMI or mTOR and PI3K inhibitors. New strategies combining these drugs with or without chemotherapy showed interesting results in metastatic and neoadjuvant trials. The selection of patients who will most benefit from these combinations is still a challenge. Currently, chemotherapy in association with anti-HER2 therapy remains the most effective treatment option.
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PMID:[Will targeted therapies replace chemotherapy?]. 2269 Apr 83

Previous studies have revealed that EGFR mutation and/or EML4-ALK gene fusion rate was higher in the non-smoker Asian females with pulmonary adenocarcinoma. The aim of this study is to determine the distribution of known oncogenic driver mutations in the female non-smoker Asian patients with pulmonary adenocarcinoma. 104 consecutively resected lung adenocarcinomas from 396 non-smoker females (less than 100 cigarettes in a lifetime) at a single institution (Tongji University, Shanghai, China) were analyzed for mutations in EGFR, EML4-ALK, KRAS, HER2, BRAF, and PIK3CA. 73 (70.2 %) tumors harbored EGFR mutations; among these, 28 were deletions in exon 19, 44 were L858R missense changes, and eight were T790M mutations. 10 (9.6 %) harbored EML4-ALK fusions, two harbored KRAS mutations, two harbored BRAF mutations, and two harbored PI3K mutations. A majority of the mutations were mutually exclusive, except two with EGFR mutation and BRAF mutation, one with EML4-ALK fusions and PI3K mutation. Thus, 82.7 % (86 of 104; 95 % CI, 75.4-90.0 %) of lung adenocarcinomas from non-smoker females were found to harbor the well-known oncogenic mutations in five genes. Lung cancer in non-smoking Asian females is a distinct entity, with majority of this subgroup being developed by the oncogenic mutations. The prospective mutation examination in this population will be helpful for devising a targeted therapy for a majority of the patients.
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PMID:Analysis of driver mutations in female non-smoker Asian patients with pulmonary adenocarcinoma. 2270 99

In this article, we will summarize some of the aspects covered by key opinion leaders at the Perspectives in Lung Cancer Congress, particularly focusing on the most recent molecular discoveries in non-small-cell lung cancer which, we believe, will have a deep impact on the clinical development of novel targeted therapies in the future. We discuss genetic alterations in squamous cell carcinoma, crizotinib therapy for ALK-positive tumors, the latest information on antiangiogenic therapies, and strategies aimed at interfering with the Ras-Raf-MEK pathway in more detail. A special emphasis is placed on the potential implications that each covered point will have for the management of advanced non-small-cell lung cancer.
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PMID:Novel molecular trends in the management of advanced non-small-cell lung cancer. 2271 89

Identifying specific somatic mutations that drive tumor growth has transformed the treatment of lung cancer. For example, cancers with sensitizing epidermal growth factor receptor mutations and echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase translocations can have remarkable responses to epidermal growth factor receptor and ALK inhibitors respectively, leading to significant clinical benefit. However, effective molecularly targeted therapies have disproportionately impacted adenocarcinomas compared to squamous cell carcinomas, and never or light smokers compared to heavy smokers. Further progress in non-small-cell lung cancer will require the identification and effective targeting of molecular alterations in all subtypes of lung cancer. Here, we review the current knowledge about the molecular alterations found in squamous cell carcinoma of the lung. First, we will discuss the ongoing efforts to comprehensively assess the squamous cell carcinoma genome. We will then discuss the evidence supporting the role of specific genes in driving squamous cell carcinomas. By describing the landscape of somatic targets in squamous cell lung cancer, we hope to crystallize the current understanding of potential targets, spur development of therapies that can have clinical impact, and underscore the importance of new discoveries in this field.
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PMID:Genetic changes in squamous cell lung cancer: a review. 2272 94

Lung cancer is in France, the leading cause of cancer death. Despite the dramatic advances that have allowed in a few years to go, for metastatic cancer, from a median survival without specific treatment of 4.5 months and now almost always more than one year, survival remains disappointing and further improvements are needed. Progress in the accumulated knowledge of the inner workings of normal and tumoral cells have paved the way for the development of targeted therapeutics called biological or simply targeted therapies. Two biological processes are already the target of marketed drugs, this is the way the receptor of epidermal growth factor (EGFR) and the path of neo-angiogenesis. It is almost assumed that, in the very near future, the inhibition of EML4-ALK will also be the subject of new drugs. In the medium term, it is conceivable that the molecular dissection of the tumors actually lead to the prescription of treatments tailored to mutations and other abnormalities that direct the growth of cancers.
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PMID:[Targeted agents in the treatment of lung cancer]. 2274 94


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