Abstract:
:Somatic alterations in the epidermal growth factor receptor gene (EGFR) result in aberrant activation of kinase signaling and occur in ∼15% of non-small cell lung cancers (NSCLC). Patients diagnosed with EGFR-mutant NSCLC have good initial clinical response to EGFR tyrosine kinase inhibitors (EGFR TKIs), yet tumor recurrence is common and quick to develop. Mechanisms of acquired resistance to EGFR TKIs have been studied extensively over the past decade. Great progress has been made in understanding two major routes of therapeutic failure: additional genomic alterations in the EGFR gene and activation of alternative kinase signaling (so-called "bypass activation"). Several pharmacological agents aimed at overcoming these modes of EGFR TKI resistance are FDA-approved or under clinical development. Phenotypic transformation, a less common and less well understood mechanism of EGFR TKI resistance is yet to be addressed in the clinic. In the context of acquired EGFR TKI resistance, phenotypic transformation encompasses epithelial to mesenchymal transition (EMT), transformation of adenocarcinoma of the lung (LUAD) to squamous cell carcinoma (SCC) or small cell lung cancer (SCLC). SCLC transformation, or neuroendocrine differentiation, has been linked to inactivation of TP53 and RB1 signaling. However, the exact mechanism that permits lineage switching needs further investigation. Recent reports indicate that LUAD and SCLC have a common cell of origin, and that trans-differentiation occurs under the right conditions. Options for therapeutic targeting of EGFR-mutant SCLC are limited currently to conventional genotoxic chemotherapy. Similarly, the basis of EMT-associated resistance is not clear. EMT is a complex process that can be characterized by a spectrum of intermediate states with diverse expression of epithelial and mesenchymal factors. In the context of acquired resistance to EGFR TKIs, EMT frequently co-occurs with bypass activation, making it challenging to determine the exact contribution of EMT to therapeutic failure. Reversibility of EMT-associated resistance points toward its epigenetic origin, with additional adjustments, such as genetic alterations and bypass activation, occurring later during disease progression. This review will discuss the mechanistic basis for EGFR TKI resistance linked to phenotypic transformation, as well as challenges and opportunities in addressing this type of targeted therapy resistance in EGFR-mutant NSCLC.
journal_name
Front Genetjournal_title
Frontiers in geneticsauthors
Shaurova T,Zhang L,Goodrich DW,Hershberger PAdoi
10.3389/fgene.2020.00281subject
Has Abstractpub_date
2020-03-27 00:00:00pages
281issn
1664-8021journal_volume
11pub_type
杂志文章,评审abstract::Germline variants of PIP4K2A impact susceptibility of acute lymphoblastic leukemia (ALL) through inducing its overexpression. Although limited reports suggested the oncogenic role of PIP4K2A in cancers, regulatory network and prognostic effect of this gene remains poorly understood in tumorigenesis and leukemogenesis....
journal_title:Frontiers in genetics
pub_type: 杂志文章
doi:10.3389/fgene.2018.00721
更新日期:2019-01-15 00:00:00
abstract::Fragile X syndrome (FXS) is mostly caused by two distinct events that occur in the FMR1 gene (Xq27.3): an expansion above 200 repeats of a CGG triplet located in the 5'UTR of the gene, and methylation of the cytosines located in the CpG islands upstream of the CGG repeats. Here, we describe two unrelated families with...
journal_title:Frontiers in genetics
pub_type: 杂志文章
doi:10.3389/fgene.2018.00442
更新日期:2018-11-02 00:00:00
abstract::Binge drinking is a widespread problem linked to increased risk for alcohol-related complications, including development of alcohol use disorders. In the last decade, binge drinking has increased significantly, specifically in women. Clinically, sexually dimorphic effects of alcohol are well-characterized, however, th...
journal_title:Frontiers in genetics
pub_type: 杂志文章
doi:10.3389/fgene.2018.00567
更新日期:2018-11-29 00:00:00
abstract::We report on three new patients with spondyloocular syndrome (SOS) in a consanguineous Pakistani family. All three patients present progressive generalized osteoporosis, short stature, recurrent fractures, hearing loss and visual impairments. WES revealed a novel homozygous frameshift variant in exon 11 of XYLT2 (NG 0...
journal_title:Frontiers in genetics
pub_type: 杂志文章
doi:10.3389/fgene.2019.00144
更新日期:2019-03-05 00:00:00
abstract::Advanced castrate-resistant prostate cancer (CRPC) is a poorly prognostic disease currently lacking effective cure. Understanding the molecular mechanism that underlies the initiation and progression of CRPC will provide new strategies for treating this deadly disease. One candidate target is the fibroblast growth fac...
journal_title:Frontiers in genetics
pub_type: 杂志文章,评审
doi:10.3389/fgene.2019.00012
更新日期:2019-01-30 00:00:00
abstract::Studies in rats and mice have established that maternal nutrition induces epigenetic modifications, sometimes permanently, that alter gene expression in the fetus, which in turn leads to phenotypic changes. However, limited data is available on the influence of maternal diet on epigenetic modifications and gene expres...
journal_title:Frontiers in genetics
pub_type: 杂志文章
doi:10.3389/fgene.2013.00049
更新日期:2013-04-05 00:00:00
abstract::Human T-lymphotropic virus 1 (HTLV-1) was the first human retrovirus to be discovered and is the causative agent of adult T-cell leukemia/lymphoma (ATL) and the neurodegenerative disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The importance of microRNA (miRNA) in the replicative cycle of ...
journal_title:Frontiers in genetics
pub_type: 杂志文章
doi:10.3389/fgene.2012.00295
更新日期:2012-12-17 00:00:00
abstract::Fibroblast growth factor 23 (FGF23), which is involved in the regulation of vitamin D, is an emerging independent risk factor for cardiovascular diseases. Previous studies have demonstrated a positive association between FGF23 and stroke. In this study, we aimed to assess the association of FGF23 with ischemic stroke ...
journal_title:Frontiers in genetics
pub_type: 杂志文章
doi:10.3389/fgene.2020.608517
更新日期:2020-12-23 00:00:00
abstract::Cardiovascular diseases are one of the prime reasons for disability and death worldwide. Diseases and conditions, such as hypoxia, pressure overload, infection, and hyperglycemia, might initiate cardiac remodeling and dysfunction by inducing hypertrophy or apoptosis in cardiomyocytes and by promoting proliferation in ...
journal_title:Frontiers in genetics
pub_type: 杂志文章,评审
doi:10.3389/fgene.2020.563166
更新日期:2020-11-20 00:00:00
abstract::The concept of Developmental Origins of Health and Diseases (DOHaD) recognizes that an unfavorable maternal environment alters the developmental trajectory of the fetus and can lead to long-term risk of developing chronic noncommunicable diseases. More recently, the concept of a paternal transmission [Paternal Origins...
journal_title:Frontiers in genetics
pub_type: 杂志文章,评审
doi:10.3389/fgene.2019.00337
更新日期:2019-04-18 00:00:00
abstract::Cardiovascular diseases are a leading cause of morbidity and mortality in Western societies. It is now well established that microRNAs (miRNAs) are determinant regulators in various medical conditions including cardiovascular diseases. The recent discovery that miRNAs, while associated with different carriers, can be ...
journal_title:Frontiers in genetics
pub_type: 杂志文章,评审
doi:10.3389/fgene.2013.00214
更新日期:2013-11-12 00:00:00
abstract::This article reviews research results and ideas presented at a special symposium at the International Association of Gerontology and Geriatrics (IAGG) Congress held in July 2017 in San Francisco. Five researchers presented their results related to infection and Alzheimer's disease (AD). Prof. Itzhaki presented her wor...
journal_title:Frontiers in genetics
pub_type: 杂志文章,评审
doi:10.3389/fgene.2018.00362
更新日期:2018-09-10 00:00:00
abstract::Extensively raised village chickens are considered a valuable source of biodiversity, with genetic variability developed over thousands of years that ought to be characterized and utilized. Surveys that can reveal a population's genetic structure and provide an insight into its demographic history will give valuable i...
journal_title:Frontiers in genetics
pub_type: 杂志文章
doi:10.3389/fgene.2015.00013
更新日期:2015-02-03 00:00:00
abstract::Extracting inherent valuable knowledge from omics big data remains as a daunting problem in bioinformatics and computational biology. Deep learning, as an emerging branch from machine learning, has exhibited unprecedented performance in quite a few applications from academia and industry. We highlight the difference a...
journal_title:Frontiers in genetics
pub_type: 杂志文章,评审
doi:10.3389/fgene.2019.00214
更新日期:2019-03-26 00:00:00
abstract::A complete and compelling evolutionary explanation for the origin of human menopause is wanting. Menopause onset is defined clinically as the final menses, confirmed after 1 year without menstruation. The theory proposed herein explains at multiple levels - ultimately genetic but involving (1) behavioral, (2) life his...
journal_title:Frontiers in genetics
pub_type: 杂志文章
doi:10.3389/fgene.2016.00222
更新日期:2017-01-06 00:00:00
abstract::Familial hemophagocytic lymphohistiocytosis Type 2 (FHL2) associated central nervous system (CNS) involvement is less understood in children, especially when considering neurologic manifestations as part of the initial presentation. We conducted a retrospective review of the clinical manifestations and genetic abnorma...
journal_title:Frontiers in genetics
pub_type:
doi:10.3389/fgene.2020.00126
更新日期:2020-03-04 00:00:00
abstract::A rapidly increasing number of reports on dysregulated long intergenic non-coding RNA (lincRNA) expression across numerous types of cancers indicates that aberrant lincRNA expression may be a major contributor to tumorigenesis. Marek's disease (MD) is a T cell lymphoma of chickens induced by Marek's disease virus (MDV...
journal_title:Frontiers in genetics
pub_type: 杂志文章
doi:10.3389/fgene.2019.01122
更新日期:2019-11-14 00:00:00
abstract::Recent advances in genomics and proteomics generated a large amount of trans regulatory data such as those mediated by RNA binding proteins (RBPs) and microRNAs. Since many trans regulators target 3' UTR of mRNA transcripts, it is likely that there would be interactions, i.e., competitive or cooperative effect, among ...
journal_title:Frontiers in genetics
pub_type: 杂志文章
doi:10.3389/fgene.2020.515094
更新日期:2020-09-08 00:00:00
abstract::Phenome-wide association studies (PheWAS) have demonstrated utility in validating genetic associations derived from traditional genetic studies as well as identifying novel genetic associations. Here we used an electronic health record (EHR)-based PheWAS to explore pleiotropy of genetic variants in the fat mass and ob...
journal_title:Frontiers in genetics
pub_type: 杂志文章
doi:10.3389/fgene.2014.00250
更新日期:2014-08-05 00:00:00
abstract::The mammalian hearing organ is a regular array of two types of hair cells (HCs) surrounded by six types of supporting cells. Along the tonotopic axis, this conserved radial array of cell types shows longitudinal variations to enhance the tuning properties of basilar membrane. We present the current evidence supporting...
journal_title:Frontiers in genetics
pub_type: 杂志文章,评审
doi:10.3389/fgene.2018.00156
更新日期:2018-05-08 00:00:00
abstract::Alzheimer's disease (AD) is a neurodegenerative and progressive disease, which often causes irreversible damages to the cerebrum. The pathogenesis of AD is far from being fully understood, while there are some popular hypotheses. So far, the diagnosis of AD relies only on clinical screening in the form of imaging tech...
journal_title:Frontiers in genetics
pub_type: 杂志文章
doi:10.3389/fgene.2019.00157
更新日期:2019-03-12 00:00:00
abstract::Tolerance to infections is defined as the ability of a host to limit the impact of a given pathogen burden on host performance. Uncoupling resistance and tolerance is a challenge, and there is a need to be able to separate them using specific trait recording or statistical methods. We present three statistical methods...
journal_title:Frontiers in genetics
pub_type: 杂志文章
doi:10.3389/fgene.2012.00262
更新日期:2012-12-14 00:00:00
abstract::Understanding the processes that cause speciation is a key aim of evolutionary biology. Lineages or biomes that exhibit recent and rapid diversification are ideal model systems for determining these processes. Species rich biomes reported to be of relatively recent origin, i.e., since the beginning of the Miocene, inc...
journal_title:Frontiers in genetics
pub_type: 杂志文章,评审
doi:10.3389/fgene.2013.00192
更新日期:2013-10-09 00:00:00
abstract::Background: Genomic regions associated with divergent livestock feed efficiency have been found predominantly outside protein coding sequences. Long non-coding RNAs (lncRNA) can modulate chromatin accessibility, gene expression and act as important metabolic regulators in mammals. By integrating phenotypic, transcript...
journal_title:Frontiers in genetics
pub_type: 杂志文章
doi:10.3389/fgene.2019.01130
更新日期:2019-11-22 00:00:00
abstract::Background and aims: Obesity is a major health problem worldwide. Given the heterogeneous obesity phenotype, an optimal obesity stratification would improve clinical management. Since obesity has a strong genetic component, we aimed to develop a polygenic risk score (PRS) to stratify obesity according to the genetic b...
journal_title:Frontiers in genetics
pub_type: 杂志文章
doi:10.3389/fgene.2019.00994
更新日期:2019-10-10 00:00:00
abstract::Amphibians are important vertebrates in toxicology often representing both aquatic and terrestrial forms within the life history of the same species. Of the thousands of species, only two have substantial genomics resources: the recently published genome of the Pipid, Xenopus (Silurana) tropicalis, and transcript info...
journal_title:Frontiers in genetics
pub_type: 杂志文章
doi:10.3389/fgene.2012.00037
更新日期:2012-03-14 00:00:00
abstract::Exosomes are biomolecular nanostructures released from cells. They carry specific biomolecular information and are mainly researched for their exquisite properties as a biomarker source and delivery system. We introduce exosomes in the context of other extracellular vesicles, describe their biophysical isolation and c...
journal_title:Frontiers in genetics
pub_type: 杂志文章,评审
doi:10.3389/fgene.2018.00092
更新日期:2018-03-27 00:00:00
abstract::Human exposure to mercury is a serious problem of public health in Amazon. As in other vulnerable populations throughout the world, Amazonian riverine populations are chronically exposed to this metal and some symptoms of mercury intoxication were already detected in these populations. However, studies on the genetic ...
journal_title:Frontiers in genetics
pub_type: 杂志文章
doi:10.3389/fgene.2018.00285
更新日期:2018-07-27 00:00:00
abstract::Mud crab, Scylla paramamosain is one of the most important crustacean species in global aquaculture. To determine the genetic basis of sex and growth-related traits in S. paramamosain, a high-density genetic linkage map with 16,701 single nucleotide polymorphisms (SNPs) was constructed using SLAF-seq and a full-sib fa...
journal_title:Frontiers in genetics
pub_type: 杂志文章
doi:10.3389/fgene.2019.00298
更新日期:2019-04-05 00:00:00
abstract::In the last decade, several studies have been focused on revealing the microRNA (miRNA) repertoire and determining their functions in farm animals such as poultry, pigs, cattle, and fish. These small non-protein coding RNA molecules (18-25 nucleotides) are capable of controlling gene expression by binding to messenger...
journal_title:Frontiers in genetics
pub_type: 杂志文章,评审
doi:10.3389/fgene.2018.00088
更新日期:2018-03-19 00:00:00